Cellular Signalling 78 (2021) 109862
Contents lists available at ScienceDirect
Cellular Signalling
journal homepage: www.elsevier.com/locate/cellsig
Biased agonism at chemokine receptors
Dylan Scott Eiger a, Noelia Boldizsar b, Christopher Cole Honeycutt b, Julia Gardner b, Sudarshan Rajagopal a,c,* a Department of Biochemistry, Duke University, Durham, NC 27710, USA b Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA c Department of Medicine, Duke University, Durham, NC 27710, USA
ARTICLE INFO ABSTRACT
Keywords: In the human chemokine system, interactions between the approximately 50 known endogenous chemokine Biased agonism ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological G protein-coupled receptors processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. Chemokine System CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies,leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specificcellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacyand safer side effect profiles.
1. Chemokine System normal and pathologic conditions. The role of CKR activation by che mokines was first recognized in the immune response, specifically as Chemokine receptors (CKRs) are a subfamily of G protein-coupled chemoattractants to direct leukocyte migration, a process known as receptors (GPCRs) that bind a group of small (8-12 kDa) and highly chemotaxis [5,6]. While the functions and roles of chemokines in leu conserved chemotactic cytokines known as chemokines [1]. The human kocytes are well known, it is now appreciated that chemokines and CKRs chemokine system is composed of approximately 20 known CKRs and 50 are also produced in a variety of non-leukocyte cell types, including known chemokines (Fig. 1). The chemokines are classified into four epithelial cells, fibroblasts,endothelial cells, and neurons [7], and play a subtypes (C, CC, CXC, CX3C) based on the number, positioning, and key role in a wide range of other cellular functions and biological pro spacing of conserved N-terminal cysteine residues [2]. Similarly, CKRs cesses including development, angiogenesis, neuromodulation, and are organized and classified according to the ligands they bind [3]. immune cell homeostasis [8–11]. For example, the expression of Chemokines are also categorized as homeostatic chemokines, which are neuronal chemokine ligands and receptors has recently been shown to constitutively expressed in a variety of specifictissues and cell types, and be involved in synaptic transmission and neuronal survival [12], as well inflammatorychemokines, which are induced during immune responses as in guidance of central nervous system (CNS) cellular interactions via primarily to recruit leukocytes to sites of inflammation[ 4]. Homeostatic neuron-astrocyte, neuron-microglia, and neuron-neuron interactions and inflammatory classifications of chemokines are not mutually [13]. exclusive, as some CKRs and chemokine ligands are involved in both Due to the chemokine system’s involvement in a wide variety of
* Corresponding author at: Box 102147, Duke University Medical Center, Durham, NC 27710, USA. E-mail addresses: [email protected] (D.S. Eiger), [email protected] (N. Boldizsar), [email protected] (C.C. Honeycutt), julia. [email protected] (J. Gardner), [email protected] (S. Rajagopal). https://doi.org/10.1016/j.cellsig.2020.109862 Received 9 September 2020; Received in revised form 7 November 2020; Accepted 24 November 2020 Available online 27 November 2020 0898-6568/© 2020 Elsevier Inc. All rights reserved. D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 biological processes, it is unsurprising that chemokines and CKRs are biased signaling for drug development in the chemokine system. implicated in various disease states including, but not limited to, auto immune disorders, infectious diseases, hypersensitivity reactions, 2. G Protein-Coupled Receptor Signaling and Biased Agonism atherosclerosis, and cancer [14–18]. The role of the chemokine system in chronic inflammatory diseases is particularly important and chemo CKRs are a subfamily of the rhodopsin class of GPCRs, the most kines play a central role in asthma, chronic obstructive pulmonary dis common and versatile superfamily of receptors in the human genome ease, inflammatory bowel disease, arthritis, multiple sclerosis, and [25] and the target of ~34% of all Food and Drug Administration (FDA) psoriasis [19]. Additionally, certain disorders are directly associated approved pharmaceutical drugs [26]. Canonical GPCR signaling starts with mutations in the genes that encode CKRs, such as the Warts, Hy with agonist binding, upon which a GPCR undergoes conformational pogammaglobulinemia, Immunodeficiency,and Myelokathexis (WHIM) changes that induce the recruitment of heterotrimeric G proteins con Syndrome which is driven by an autosomal dominant truncation mutant sisting of Gα, Gβ, and Gγ subunits. The guanosine diphosphate (GDP)- in the receptor CXCR4 [20]. bound Gα subunit undergoes nucleotide exchange for guanosine While the chemokine system is known to play a significant role in triphosphate (GTP), leading to Gα activation and dissociation of the many disease states, there are relatively few drugs that target it directly. heterotrimeric complex into its Gα and Gβγ constituents [27]. The Gα Chemokines and CKRs bind with significantpromiscuity, wherein most subunits are classified into four families based on sequence similarity: CKRs can be activated by multiple chemokine ligands and most che Gαs, Gαi/o, Gαq/11, and Gα12/13 [28]. The activated Gα proteins typically mokines can activate multiple CKRs [21]. This promiscuity was thought regulate the production and subsequent signaling of secondary mes to lead to “redundancy” between chemokines and their receptors, sengers, such as adenosine 3’,5’-cyclic monophosphate (cAMP), intra serving as a mechanism for a robust physiologic response [22]. As cellular calcium, and inositol triphosphate [29]. Most chemokine adequate chemokine levels are imperative for immune cell function, receptors signal through Gαi/o, which inhibits adenylyl cyclase and re redundant chemokine signaling would provide sufficient signals to duces intracellular concentrations of cAMP [30]. There are various direct leukocyte chemotaxis and function that is relatively insensitive to isoforms of the Gβ and Gγ subunits, and at chemokine receptors the Gβγ variations in the concentration of any individual chemokine [23]. dimer has been shown to activate phosphoinositide-specific phospholi However, we now appreciate that many of these ligands can have pase Cβ (PLC) and phosphoinositide 3-kinase (PI3K). PLC then produces distinct signaling profiles at the same receptor and many receptors can diacylglycerol (DAG), leading to the activation of protein kinase C have distinct signaling profiles when stimulated by the same ligand, a (PKC), and inositol-triphosphate (IP3), which triggers calcium mobili phenomenon referred to as “biased agonism” [22,24]. Biased signaling zation [31]. The signaling messengers of the Gβγ dimer in chemokine through differences in ligands, receptors and the cellular context (sys receptors have been demonstrated to play a role in the promotion of tem) can have important effects on chemokine signaling and implica leukocyte migration, among other functions [32]. tions for drug development. Here, we review the current literature on Following G protein activation, G protein-coupled receptor kinases biased signaling within the chemokine system to highlight the complex (GRKs) are recruited to the receptor and phosphorylate the receptor C- and multidimensional nature of biased agonism and the biochemical terminus and intracellular loops. This phosphorylation promotes the mechanisms that underlie it, the importance of biased agonism within interaction of the receptor with the β-arrestins, which were first the chemokine system and its physiologic effects, and the implications of described for their function in the desensitization of G protein-mediated
Fig. 1. The complexity of the human chemokine system. Chemokine receptors fall into fivecategories: CCRs, CXCRs, ACKRs, XCRs and CX3CRs. Chemokine ligands fall into four categories: CCLs, CXCLs, XCLs, CX3CLs. Lines connecting chemokine receptors to chemokines are colored for clarity.
2 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 signaling through steric hindrance of the receptor [33]. β-arrestins act as as different G proteins or β-arrestins, referred to as “pluridimensional multifunctional adaptor proteins and are involved in a variety of other efficacy” [41], it was soon discovered that many agonists were capable cellular process such as receptor internalization, transactivation, traf of signaling with different efficaciesto their downstream effectors [42]. ficking,and signaling [34]. β-arrestins are capable of signaling through a Initially these examples were thought to be rare, but studies over the variety of mediators including mitogen-activated protein kinases past fifteenyears have demonstrated that, across a wide variety of GPCR (MAPKs), nuclear factor κB (NF-κB), protein kinase B (Akt), and Src subtypes, different ligands for the same receptor can activate specific tyrosine kinase, thereby activating distinct signaling pathways inde and distinct signaling pathways downstream. These examples can range pendent of G protein-mediated signaling [35–39]. At some chemokine from mild bias, with slight differences in preferences for different G receptors, such as CXCR4 and CCR5, it has even been shown that in the proteins, to completely biased ligands which preferentially activate G absence of G protein coupling, β-arrestin-bound CKR complexes are still protein signaling pathways (G protein-biased) while not activating able to induce receptor endocytosis and signaling [40]. β-arrestin signaling (β-arrestin-biased) pathways, or vice versa (Fig. 2A- C). 3. Biased Chemokine Signaling Biased agonism within the chemokine subfamily was firstdescribed at CCR7, where it was demonstrated that the receptor’s two endogenous With the ability of GPCRs to signal through multiple pathways such ligands—CCL19 and CCL21—both could activate G protein-dependent
Fig. 2. Biased agonism at G Protein-Coupled Receptors. Signaling at G Protein-Coupled Receptors can be driven by ligands that are (A) balanced and equally activate both G protein and β-arrestins, (B) those that signal primarily through heterotrimeric G proteins (G protein-biased), or (C) those that signal primarily through β-arrestin adapter proteins (β-arrestin-biased). Biased agonism can be achieved through (D) biased ligands, (E) biased receptors, or (F) biased systems
3 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 signaling cascades but only CCL19 was capable of activating β-arrestin another method for a system to finely tune chemokine signaling. dependent signaling [43–46]. Since then, numerous studies have Another mechanism that can regulate chemokine activity is post- demonstrated that the chemokine system is not redundant, but rather translational modification, such as proteolytic processing, citrullina highly specificin its cellular outputs, part of which can be attributed to tion and glycosylation [59]. While these modificationshave been shown biased agonism [39]. Functional and structural demonstrations of bias in to regulate chemokine activity, it is largely unknown at this time as to chemokine signaling provide support for the notion that the promiscuity whether they have an effect on ligand bias. of the chemokine system is not redundant, but suggests high levels of Beyond simple G protein vs β-arrestin bias, there are examples of bias signaling specificity by allowing individual chemokines and CKRs to between specific G protein subtypes or β-arrestin isoforms [60,61]. induce functionally distinct biochemical, cellular, and physiologic out Various analogs of CCL5 analyzed by Lorenzen et al. at CCR5 signal comes [24]. Biased agonism in the chemokine system can be a result of through Gαi/o with similar efficacies,whereas they vary widely in their signaling through each component of the GPCR ternary complex: the ability to signal through Gαq, suggesting that bias between G protein ligand, the receptor, and the transducer (“system”) elements (Fig. 2D-F). subtypes may affect signaling at receptors able to couple to multiple With ligand bias, different ligands binding to the same receptor generate downstream transducer elements [60]. While investigation into bias distinct responses. With receptor bias, the same ligand binding to between Gα subtypes is difficult due to cross-talk between different G different receptors generates distinct responses. With system bias, a protein signaling pathways, bias between different G proteins presents different cellular context, e.g., differential transducer expression in a an added layer of complexity to ligand bias in the chemokine system. different cell type, results in a change in GPCR signaling. While the exact mechanisms and functional consequences of these layers of bias are 3.2. Receptor Bias incompletely understood, it is possible that this complexity allows for highly specificand coordinated physiologic responses. Additionally, the Receptor bias refers to a receptor that demonstrates preferential interplay between these individual sources of biased agonism can interaction with certain transducers over others [39]. ACKR3, also theoretically generate a multitude of permutations of known as CXCR7, was originally characterized as a “decoy” receptor immunophenotypes. that served to modulate CXCR4 signaling by either sequestering excess CXCL12 (as both ACKR3 and CXCR4 can bind CXCL12) or serving as a 3.1. Ligand Bias coreceptor with CXCR4, rather than activating specific downstream signaling pathways [62–65]. However, it was later discovered that Ligand bias is arguably the most widely studied mechanism of bias in ACKR3 not only acted as a decoy receptor, but also was capable of the chemokine system. Ligand bias refers to the phenomenon in which a independently signaling via β-arrestins [66]. CXCR4 and ACKR3 signal molecule binds to a receptor and promotes an ensemble of receptor through different pathways despite being activated by the same ligand, conformations that preferentially interact with some transducers over with CXCR4 activating both G proteins and β-arrestins and ACKR3 others [39]. For example, the two endogenous ligands of CCR7, CCL19 signaling only via β-arrestins; therefore ACKR3 acts as a β-arrestin biased and CCL21, induce G protein activation and signaling to similar extents, receptor relative to CXCR4 [67]. Additional studies have shown that but CCL19 induces β-arrestin recruitment to CCR7 significantly more ACKR3 also serves as a receptor for endogenous opioids, contributing to than CCL21 [44–46]. Additionally, receptor internalization and circadian glucocorticoid oscillations [68] and acting as a decoy for chemotaxis induced by CCL19, but not CCL21, are reduced following opioids in the brain [69]. Interestingly, recent work has demonstrated siRNA knock down of β-arrestin 2 and both β-arrestin 1 and β-arrestin 2, that β-arrestin recruitment to ACKR3 is dispensable for some receptor respectively [46]. Other assays assessing β-arrestin trafficking,receptor functionality. Montpas et al. show that both siRNA knockdown of desensitization, MAPK signaling, and receptor phosphorylation are β-arrestin 1 and or β-arrestin2 in HEK293 cells does not impact ACKR3 significantly different following agonist stimulation with CCL19 or mediated degradation of CXCL11 or CXCL12 [70]. They repeated these CCL21 [44], consistent with CCL19 acting as a β-arrestin biased ligand studies in β-arrestin 1 and 2 knockout murine embryonic fibroblasts relative to CCL21. Similar to the ligands of CCR7, the endogenous li (MEFs) and also saw that ACKR3 chemokine scavenging was unaffected. gands of CXCR3 also exhibit ligand bias. In previous work performed by Similarly, Saaber et al. demonstrate that ACKR3 chemokine scavenging our group, these endogenous ligands exhibit both varying levels and and endocytosis is dependent on receptor phosphorylation but inde distinct patterns of interactions with β-arrestin [24]. When stimulating pendent of β-arrestins. Utilizing a variety of transgenic mice, they CXCR3A, CXCL11 recruits β-arrestin at a significantly higher level further demonstrate that β-arrestin is dispensable and receptor phos compared to CXCL10, even though the two ligands activate Gαi to phorylation is indispensable in ACKR3 mediated migration of cortical similar levels [47]. Furthermore, CXCL11 demonstrates a class B pattern interneurons [71]. These findings demonstrate that ACKR3, while of β-arrestin recruitment, one of which promotes a stable β-arrestin: technically a β-arrestin-biased receptor as it does not signal via hetero GPCR complex with trafficking of β-arrestin into endosomes, while trimeric G proteins, has functionality independent of the β-arrestins, CXCL9 and CXCL10 demonstrate a class A pattern of recruitment, which highlighting the complexity of biased agonism at GPCRs. promotes a transient β-arrestin:GPCR complex limited to the plasma Alternative splicing of GPCR transcripts further increases receptor membrane [24]. Multiple chemokine receptors and their endogenous diversity and the potential for receptor bias [72]. Highly truncated re ligands demonstrate similar degrees of biased agonism, including CCR1, ceptor splice variants with only three transmembrane domains have CCR5, CCR10, CXCR1, and CXCR2 [24,43,48–52]. been shown to heterodimerize with their wild type counterparts and Ligand bias has also been demonstrated to depend on the oligomeric retain them in the endoplasmic reticulum, while longer splice variants state of chemokines. In vivo, chemokines homo-oligomerize and exist in with a preserved seven transmembrane architecture have been shown to an equilibrium between their monomeric and dimeric forms [53], with promote signaling via distinct signal transduction pathways [72]. The the monomer frequently serving as the active form that binds the re isoforms of CXCR3 present an example of how alternative splicing can ceptor and the dimeric form bound to glycosaminoglycans [54]. lead to endogenous receptor bias [47,73]. CXCR3 has three splice var Changes in the overall oligomeric state of chemokines are critical for iants: CXCR3A, CXCR3B, and CXCR3-alt [73]. CXCR3A and CXCR3B their cellular functions, reflected by the differential signaling profiles have nearly identical sequences, with the only difference being that between their monomeric and dimeric forms [55–58]. Drury et al. found CXCR3B possesses an extra 51 amino acids on its extracellular N ter that at CXCR4 the monomeric form of CXCL12 is β-arrestin biased minal domain [73]. CXCR3alt has both truncated forms of the third relative to its dimeric form, and this bias mediates increased levels of intracellular loop and transmembrane helices 6 and 7, resulting in a chemotaxis and differential MAPK activation kinetics [55]. Modulation highly truncated 5 transmembrane receptor [73]. CXCR3alt does not of the monomer-dimer equilibrium in vivo may consequently serve as recruit β-arrestin or stimulate a Gαi response, but promotes modest
4 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 extracellular signal-regulated kinase (ERK) phosphorylation and be functionality [76,80]. comes internalized following ligand stimulation [73]. The two func tional CXCR3 splice variants CXCR3A and CXCR3B have significantly 4. Biochemical Mechanisms of Biased Agonism biased responses from one another [47,73]. CXCR3B is β-arrestin-biased relative to CXCR3A, as the two isoforms similarly recruit β-arrestin upon As discussed above, the ternary complex of ligand, receptor, and stimulation with CXCL11 but CXCR3A signals through Gαi to a signifi transducer serves as a model for the components driving biased agonism cantly greater extent [47]. Their specificinteractions with β-arrestin also [39]. A finalcellular output is highly dependent on (1) the ligand, (2) the differ, as CXCR3A’s interaction with β-arrestin demonstrates a stable receptor, and (3) the transducer elements in the context of the cellular class B receptor pattern while CXCR3B’s demonstrates a transient system. These three elements are the ultimate facilitators of biased interaction, consistent with class A receptor behavior [47]. Smith et al. signaling, and understanding the structural and functional bases of their also found differences in receptor kinetics and mechanisms driving ERK interactions is integral to understanding potential mechanisms of biased phosphorylation and receptor internalization. Finally, the two variants agonism. display differential ligand induced transcriptional activity, as stimula tion of CXCR3A, but not CXCR3B, with CXCL11 resulted in a robust 4.1. Ligand-Receptor Interactions response using serum response element (SRE) and serum response factor-response element (SRF) transcriptional reporters. These and other At the most fundamental level, ligand binding promotes an ensemble examples suggest that there are a number of finely tuned mechanisms of receptor conformations that promote differential transducer coupling, that allow receptor bias to differentially regulate the response to leading to the selective activation of specific signaling pathways over chemokines. others. Recent crystal structures and cryoEM have changed our under standing of how chemokines bind to their receptors [85]. In the classic 3.3. System Bias two-site model for chemokine binding, a chemokine binds its receptor through two distinct chemokine recognition sites (CRS), CRS1 and System bias is primarily regulated through the differential expression CRS2. CRS1 consists of an interaction between the sulfated tyrosines of or function of receptor and transducer elements, which consequentially the receptor N-terminus with the chemokine globular core, and CRS2 promote biased cellular outputs [39]. These include every element of the consists of an interaction between the transmembrane regions of the signal transduction cascade, from proximal effectors such as GRKs, G receptor with the chemokine N-terminus. Crystal structures have proteins and β-arrestins, to other proteins that regulate second demonstrated an intervening CRS1.5 between CRS1 and CRS2 at a messenger responses, such as Regulator of G Protein Signaling (RGS) and conserved Pro-Cys of the CKR N-terminus against the conserved disul Activator of G Protein Signaling (AGS) proteins, to all of the downstream fide of the chemokines [86,87]. signal transduction machinery. This phenomenon manifests as observed Affecting CRS2 by mutating chemokine N termini has been shown to differences in signaling events between cell types. For example, the affect biased signaling responses at CCR1, with data demonstrating that functional effects of mutations on CXCR6 receptor function and selec this region has a role in stabilizing active receptor conformations that tivity of Gi/o proteins are cell-type specific[ 74]. In an F128Y mutant of contribute to biased agonism [51]. CCR1 is known to bind at least nine CXCR6, the receptor’s dependence on Go proteins was diminished in different endogenous chemokines including CCL7, CCL8, and CCL15. HEK-293T cells, but resembled that of the wild type receptor in Jurkat Sanchez et al. showed that CCL7 and CCL8 demonstrate bias towards Gαi E6-1 cells [74]. Outside of the chemokine system, it has been shown that signaling relative to CCL15(∆26), an N-terminal truncated version of β-arrestin biased agonists for the dopamine receptor D2 demonstrate CCL15 that renders it approximately the same length as CCL7 and CCL8. different signaling effects in the striatum and prefrontal cortex due to To elucidate the structural basis of this bias, Sanchez et al. created a differential expression of GRK2 and β-arrestin 2 [75]. While, to our chimeric chemokine, CCL15(N-CCL7), which consists of CCL15 with the knowledge, system bias in the chemokine system has not been rigorously N terminal region of CCL7. Using radioligand binding, CCL15(N-CCL7) and explicitly studied, changes in GRK expression have been proven to had a binding affinity for CCR1 nearly identical to CCL7 and signifi alter the functionality of numerous chemokine receptors [76]. For cantly lower than CCL15(∆26). When looking at G protein activation, example, murine T cells with a 50% reduction of GRK2 levels experi CCL15 (N-CCL7) demonstrated a signaling profilevery similar to that of enced significantly more migration, calcium flux, protein kinase B ac CCL15(∆26) which suggests that the N-terminal regions of CCL7 and tivity, and ERK phosphorylation upon stimulation with chemokine CCL15(∆26) are equally capable of driving G protein activation. How ligands than in wild type cells [77]. Similarly, Arnon et al. created ever, CCL15 (N-CCL7) shows an intermediate ability to recruit β-arrestin GRK2f/- mice carrying a T cell-specificor a B cell specificcre to study the when compared to CCL15(∆26) and CCL7, suggesting that the N-ter effects of GRK2 on S1P receptor-1 function in lymphocyte migration minal regions of CCL7 and CCL15(∆26) contribute to a chemokines [78]. They found that T and B cell movement from the blood into ability to recruit β-arrestin [51]. Sanchez et al. also found that short lymphatic tissues was reduced in the absence of GRK2, and that B cells ening CCL15(∆26) [26] by only two residues, CCL15(∆28) [28], did not between the splenic marginal zone and follicle were also reduced. These affect the chemokines affinity for the receptor, but drastically reduced findings have physiologic implications, as GRK expression is differen its maximum ability to recruit β-arrestin without affecting its potency. tially modulated in various disease states. For example, the expression Concurrently, this shortening increased its potency but not maximum levels of GRK2 and GRK5 are elevated in the lungs of rats treated with IL- ability to inhibit cAMP accumulation. These data demonstrate the 1β, while levels of GRK2 and GRK6 are reduced in mice in an experi importance of a chemokine’s N-terminal length and sequence identity mental autoimmune encephalomyelitis (EAE) animal model [79]. not only in binding affinity, but also in stabilizing receptor conforma Furthermore, downregulated GRK2 and GRK6 have been found in pa tions that differentially interact with both G proteins and β-arrestins. tients with autoimmune diseases such as multiple sclerosis and rheu Research exploring the endogenous ligands of CXCR3 suggests that matoid arthritis, and dynamic expression of β-arrestin 1 has been found each ligand exhibits differential binding interactions with the receptor, in mouse models of both EAE and an adjuvant-induced arthritis [80–84]. further implicating the CRS2 interface in a biased response. Cox et al. It is inherently difficultto accurately recapitulate the dynamic in vivo used radioligand binding studies to suggest that CXCL9 and CXCL10 expression levels of transducer elements across various cell types in vitro. bind at a separate site on the receptor than CXCL11 [88]. Colvin et al. However, considering the diversity of chemokine receptors and immune performed mutagenic studies on CXCR3 and elucidated which residues cells within mammals, and the dynamic nature of GPCRs and GPCR were implicated in this differential chemokine binding [89]. Whereas transducer elements in inflammatoryconditions, system bias likely adds deletion of the 16 proximal N terminal amino acids of the receptor a significant layer of complexity to the chemokine system’s biased resulted in diminished calcium flux, actin polymerization, and
5 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 chemotaxis upon stimulation with CXCL10 and CXCL11, activity stim of the receptor [93]. Wasilko et al. speculate that this differential ulated by CXCL9 was not affected [89]. Together, these seemingly binding pattern is due to CCL20’s short N terminal region, which con discordant results highlight the diversity in activation mechanisms at a sists of only 5 amino acids. Work from Riutta et al. further supports this single receptor and the importance of ligand and receptor identity, as notion as they manipulated various aspects of CCL20’s short N terminal well as the interactions between ligand, receptor, and transducer ele region and determined that CCL20 binding and activation of CCR6 is ments in determining the overall final cellular output. highly tolerant to changes in the length and identity of the N terminus Different receptors can display different binding patterns to the same [94]. Other chemokines or ligands with shorter N termini could prove to ligand, further pointing to how this interaction contributes to biased exhibit binding patterns similar to CCL20, emphasizing the notion that signaling. For example, while the receptor CXCR4 and β-arrestin biased chemokine binding is extremely diverse and that attempting to gener receptor ACKR3 are both capable of binding CXCL12, mutagenic studies alize chemokine ligand-receptor interactions to a single model may be have revealed that the ligand-receptor interface of CXCR4 is signifi impossible. The interactions between the chemokine ligands and re cantly different than that of ACKR3 [90,91]. Jaracz-Ros et al. created a ceptors have thus been proven to be multi-site, complex, and dynamic. variety of CXCL12 mutants and demonstrated that substitution of N- terminal amino acids decreased receptor affinity at both CXCR4 and 4.2. Phosphorylation Barcode ACKR3. However, while N-terminal truncations of CXCL12 similarly led to decreased receptor affinityat CXCR4, these truncation mutants were Receptor activation via ligand binding leads to a conformational unable to bind to ACKR3. Interestingly, CXCL12 substitution mutants change in the receptor which translates into a cellular response first displayed a decreased ability to drive receptor internalization at CXCR4 through G protein recruitment and activation, followed by phosphory when compared to WT CXCL12 but had no impact on internalization at lation of the intracellular loops and C terminus of the receptor. This ACKR3 [90]. Similarly, these substitution mutants demonstrate no phosphorylation leads to the tight binding of the β-arrestins, which β ability to recruit -arrestin to CXCR4, but show slightly decreased po abrogate G protein signaling and also initiate β-arrestin dependent β tency and efficacy in -arrestin recruitment at ACKR3 relative to WT signaling cascades. Phosphorylation patterns of the receptor can vary CXCL12. Notably, both ACKR3 and CXCR4 bind CXCL12 through the based on the identity of the ligand used to activate the receptor and the receptor distal N-terminus wrapping around the chemokine, forming a kinases present in the cell, and these differential phosphorylation pat novel CRS0.5 interface [86,92]. terns can promote engagement with distinct transducer elements, and A recent cryoEM structure of CCL20 bound to CCR6 further illus consequently generate a unique signaling cascade (Fig. 3). Numerous trates that chemokine receptors possess extremely diverse mechanisms studies support this model, known as the “barcode hypothesis,” as one of activation. Numerous class A GPCRs have been shown to exhibit a mechanistic explanation that underlies biased agonism [95–98]. deep binding pocket mode of activation that involves interactions with Formation of the phosphorylation barcode is mediated by a number the transmembrane receptor core and proximity to the toggle switch of kinases, most notably G protein-coupled receptor kinases, or GRKs motif, a tryptophan residue that has been shown to contribute to [99]. There are seven GRK isoforms, but only GRK2, 3, 5, and 6 are conformational changes upon receptor activation [93]. In contrast, expressed ubiquitously and are primarily relevant for a discussion of CCL20 binds in a long, shallow extracellular site distal from the toggle bias in the chemokine system [99]. GRKs are selective in the residues switch [93]. CCL20 does not require interactions between its N terminus they phosphorylate, implicating them in the complexity required for a and the 7 transmembrane receptor core to activate CCR6, but instead biased response. Peptide studies reveal that different classes of GRKs requires major interactions with extracellular loop 2 and the N terminus have varying affinities for phosphorylating sites within different
Fig. 3. Phosphorylation barcode promotes differential downstream signaling. Distinct patterns of G Protein-Coupled Receptor phosphorylation can promote dif ferential downstream signaling cascades. (A) A phosphorylation barcode which preferentially drives β-arrestin activation of with effector “A” while (B) demonstrates a phosphorylation barcode which preferentially drives β-arrestin mediated activation of effector “B”.
6 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 proximities of acidic or basic residues [100]. For example, GRK5 and internalization was dependent on phosphorylation of intracellular loop GRK6 preferentially phosphorylate peptides with basic amino acids near 3 [111]. Similarly, the C terminal tail of CCR7 is required for chemo the N terminal side of the target residues [101,102]. Furthermore, GRKs taxis, calcium flux, and ERK1/2 phosphorylation, but not receptor have also been shown to phosphorylate specific residues on the C ter internalization nor recycling [112]. Because biased ligands drive their minal tails of chemokine receptors [103]. Upon stimulation with distinct signaling profiles via the receptor, it can be postulated that CXCL12, CXCR4 is rapidly phosphorylated by GRK6 at Ser-324/5 and biased signaling is also critically dependent on the differential in Ser-339, and slowly phosphorylated by GRK6 at Ser-330 [103]. Data teractions between the receptor and its transducers. also suggests that phosphorylation sites at CXCR4 are hierarchical and Distinct conformations of transducer elements can lead to varying sequential in nature, in which a certain order of phosphorylation is cellular responses. Both synthetic and endogenous β-arrestin biased li necessary to induce a response [104]. Therefore, the pattern of phos gands of CXCR3A induced a conformational change in β-arrestin upon phorylation mediated by distinct GRKs on the receptor C-terminal tail stimulation, suggesting that transducer conformation plays a role in appears to be specific and coordinated. their biased response [15,47]. Mutation of transducers has helped Genetic knockdown of GRKs has connected specific classes of GRKs determine which structures are involved in specific signaling events. to distinct cellular functions both in vitro and in genetically modified Cahill et al. demonstrated that β-arrestin assumes at least two distinct mice [44,47,95,105,106]. At CXCR4, for example, GRK2 and GRK6 have conformations when bound to a GPCR: a tail conformation or a core been shown to negatively regulate calcium mobilization. Additionally, conformation [113]. The “tail” conformation interacts with the C ter ERK1/2 phosphorylation is negatively regulated by GRK2, but positively minal tail of the receptor, while the “core” conformation involves the regulated by GRK3 and GRK6 [103]. Furthermore, GRK3 is responsible finger-loop region of β-arrestin and the seven transmembrane receptor for the phosphorylation of the two most distal phosphorylation sites on core. A β-arrestin mutant lacking the finger loop region required for the CXCR4 C terminal tail, which have been implicated in β-arrestin assuming the “core” conformation was unable to desensitize G protein recruitment [106]. Similarly, Zidar et al. found that, at CCR7, CCL19- mediated signaling, even though it was still able to induce receptor mediated β-arrestin recruitment was reduced following siRNA knock internalization and other β-arrestin dependent signaling effects [113]. down of GRK3 and GRK6, while CCL21-mediated β-arrestin recruitment This directly connects specific conformations of transducer isoforms to was only reduced following GRK6 knockdown [44]. Additionally, GRK6 cellular functions, suggesting that preferential stabilization of certain knockdown led to a significant decrease in ERK 1/2 phosphorylation at conformations could be the basis of a biased signaling response. both chemokines, while GRK2 and GRK3 knockdown led to an increase Furthermore, the varying functional effects of transducer confor in ERK 1/2 phosphorylation only with CCL19 [44]. Instances of differ mations may be the basis of the functional selectivity of the two ential involvement by GRKs also occur between the aforementioned β-arrestin isoforms. These two isoforms, β-arrestin 1 (arrestin-2) and splice variants of CXCR3 [47]. CXCR3B driven recruitment of β-arrestin β-arrestin 2 (arrestin-3), despite possessing significant sequence simi involves GRK2 and GRK3 but not GRK5 nor GRK6, while that of CXCRA larity, have been shown to promote distinct cellular functions [114]. For involves all four kinases [47]. These data are consistent with a model in example, β-arrestin 2 is more heavily involved in receptor desensitiza which different expression levels of these kinases can influencea biased tion than β-arrestin 1 when interacting with the vasopressin 2 receptor, response. The utilization of different GRK isoforms by biased ligands and and β-arrestin 1 accumulates in the nucleus while β-arrestin 2 does not receptors to produce a phosphorylation barcode could lead to func [115]. β-arrestin1 and β-arrestin 2 have different conformations when in tionally distinct pools of β–arrestins, thus yielding important insights complex with a phosphorylated receptor, with the main difference into the mechanism of biased agonism. resting in the interaction with the receptor core [115]. Mutational an alyses of the two isoforms suggest that the core interactions are the basis 4.3. Receptor-Transducer Interactions of their differential desensitization, supporting the notion of linking β-arrestin-receptor interactions to distinct functional consequences Upon stimulation with a ligand, a GPCR recruits transducer elements [113,115]. to induce signaling cascades. Potential for bias rests in the receptor- Ligand-receptor interactions, receptor-transducer interactions, and transducer interactions in a similar fashion as the ligand-receptor the phosphorylation barcode each present unique insight into eluci interaction; receptors have the potential to stabilize interactions with dating the means through which a biased response is produced. The or conformations of transducer elements that lead to distinct signaling mechanisms of biased agonism illustrate the significant potential for responses. Recent structural studies have provided important insights their involvement in the diverse functions within the chemokine system. into how such structural changes can be linked to receptor activity and biased responses. Crystal structures of negative allosteric modulators 5. Functional Effects of Chemokine Bias bound to the chemokine receptors CCR2 [107] and CCR9 [108] have demonstrated an allosteric binding site on the intracellular surface. This While much is known regarding the biochemical mechanisms un binding site involves several conserved amino acid residues and is a derlying biased chemokine signaling, there is relatively less known common intracellular binding site in class A GPCRs [109]. Notably at the about the functional consequences of such signaling. Table 1 lists type 1 angiotensin II receptor, Wingler et al. found that G-protein biased selected endogenous and synthetic chemokine receptor ligands and their agonists stabilize an “open” conformation of the intracellular surface of functional consequences at CKRs. It is difficult to completely assess the receptor, while β-arrestin biased agonists stabilize a more closed ligand, receptor, and systems bias in vitro when considering the vast receptor intracellular conformation [110]. This suggests that biased diversity of tissue types in which the chemokine system is expressed, as agonists promote differential interactions with transducers through the well as the variety of functions of the chemokine system under both generation of specificreceptor intracellular conformations, which could homeostatic and inflammatoryconditions. Therefore, it is important for potentially be targeted with novel allosteric modulators. However, at future research to use in vivo examples of biased agonism to direct in vitro this time there is little structural information on the mechanisms un studies that aim to understand the mechanisms underlying this derlying biased agonism by chemokine receptors, although there is a signaling. We highlight some examples below. large body of work that have studied how receptor-transducer in teractions contribute to biased signaling. 5.1. CXCR3 Colvin et al. found that the endogenous ligands of CXCR3 promote signaling through different structural elements of the receptor [111]. Mechanisms and functional effects of biased agonism are especially + CXCL9- and CXCL10-induced internalization was dependent on the well-characterized at CXCR3 in activated CD8 T cells. CXCL11 pro phosphorylation of the receptor C terminus, whereas CXCL11-induced motes significantly greater chemotactic response when compared to
7 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 Selected studies of endogenous and synthetic chemokine ligands. Highlighted compounds are those at which biased agonism has been demonstrated.
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
CXCR1 CXCL6 In vitro G protein signaling [24,170] CXCL8 β-arrestin recruitment Receptor internalization (R)-Ketoprofen Antagonist In vitro Chemotaxis [171] Reparixin (Repertaxin) Allosteric antagonist In vitro Chemotaxis [172,173]
In vivo Inflammation Reperfusion injury Blood pressure DF 2156A Allosteric antagonist In vitro G protein signaling [174] Chemotaxis Cell proliferation
In vivo Angiogenesis Hepatic reperfusion injury SX-517 Antagonist In vitro G protein signaling [175]
In vivo Inflammation CXCR2 CXCL1 In vitro G protein signaling [24,170] CXCL2 β-arrestin recruitment CXCL3 Receptor internalization CXCL5 CXCL6 CXCL7 CXCL8 SB 455821 Antagonist In vitro Chemotaxis [176]
In vivo Neutrophil migration Reparixin Allosteric antagonist In vitro Chemotaxis [172,173] (Repertaxin) In vivo Inflammation Reperfusion injury Blood pressure DF 2156A Allosteric antagonist In vitro G protein signaling [174] Chemotaxis Cell proliferation
In vivo Angiogenesis Hepatic reperfusion injury Navarixin (MK-7123) Antagonist In vivo COPD [177–179] Solid tumors Danirixin Antagonist In vitro G protein signaling [180–182]
In vivo Neutrophil migration and activation COPD SB225002 Antagonist In vitro Neutrophil chemotaxis [183,184]
In vivo Neutrophil margination Colitis Inflammatory bowel syndrome SX-517 Antagonist In vitro G protein signaling [175]
In vivo Inflammation AZD5069 Antagonist In vitro Neutrophil chemotaxis [185]
In vivo Acute lung inflammation CXCR3 CXCL4 In vitro G protein signaling [24,89,111,119,186,187] CXCL9 β-arrestin recruitment CXCL10 Receptor internalization CXCL11 Chemotaxis CCL7 (Antagonist) CCL11 In vivo T cell polarization (Antagonist) T cell localization VUF1066 Agonist In vitro G protein signaling [188,189] VUF11418 Agonist β-arrestin recruitment Receptor internalization GRK engagement Chemotaxis
Chemotaxis In vivo Inflammation (continued on next page)
8 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 (continued )
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
FAUC1036 Allosteric agonist In vitro G protein signaling [190] FAUC1104 Allosteric agonist β-arrestin recruitment Receptor internalization Chemotaxis BD103 Allosteric modulator In vitro G protein signaling [191] BD064 Allosteric modulator β-arrestin recruitment cRAMX3 Antagonist SCH546738 Antagonist In vitro G protein signaling [192,193] Chemotaxis
In vivo Mouse collagen induced arthritis Rat experimental autoimmune encephalitis Rat Cardiac transplantation 8-azaquinazolinone derivative Allosteric modulator In vitro G protein signaling [194] β-arrestin recruitment CXCR4 Monomeric/ In vitro G protein signaling [55,195,196] dimeric β-arrestin recruitment CXCL12 Chemotaxis
EPI-X4 In vivo Cancer metastasis (Antagonist) Hematopoietic stem cell mobilization Plerixafor (AMD3100) Allosteric antagonist In vitro G protein signaling [136,137,168,197] β-arrestin recruitment X4-2-6 Receptor internalization Allosteric antagonist Chemotaxis
In vivo Hematopoietic stem cell mobilization TG-0054 (burixafor) Antagonist In vivo Hematopoietic stem cell [198–200] mobilization Choroid neovascularization Inflammation Cardiac function AMD11070 Antagonist In vivo X4-trophic HIV-1 infection [201–205] (mavorixafor) Inflammation WHIM syndrome Melanoma MSX-122 Antagonist In vitro G protein signaling [206,207] Chemotaxis Angiogenesis
In vivo Inflammation Breast cancer metastasis Solid tumors CTCE-9908 Antagonist In vivo Solid tumors [208] POL-6326 Antagonist In vivo Hematopoietic stem cell [209] mobilization RSVM Agonist In vitro Chemotaxis [210] ASLW Superagonist Receptor cell surface expression ATI-2341 Allosteric agonist In vitro G protein signaling [211–213] β-arrestin recruitment GRK engagement Chemotaxis Neutrophil mobilization Receptor internalization DV1-K-(DV3) Antagonist In vitro G protein signaling [214] Chemotaxis X4-tropic HIV-1 infection T22 Antagonist In vitro G protein signaling [215] X4-tropic HIV-1 infection POL6326 (Balixafortide) Antagonist In vivo Hematopoietic stem cell [216–218] mobilization HER2 negative, locally recurrent or metastatic breast cancer T140 Inverse agonist In vitro X4-tropic HIV-1 infection [219] CXCL12-T140 chimera Agonist In vitro Chemotaxis [220] CXCL12-IT1t chimera Antagonist In vitro G protein signaling [221] β-arrestin recruitment Chemotaxis PZ-218 Antagonist In vitro G protein signaling [222,223] Chemotaxis (continued on next page)
9 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 (continued )
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
In vivo Leukocytosis 508MCI Antagonist In vitro G protein signaling [224]
In vivo Inflammation Tumor metastasis GSK812397 Antagonist In vitro Chemotaxis [225] X4-tropic HIV-1 infection TIQ-15 Antagonist In vitro G protein signaling [226] β-arrestin recruitment X4-tropic HIV-1 infection IT1t Allosteric antagonist In vitro Chemotaxis [227,228]
In vivo X4-tropic HIV-1 infection ALX40-4C Antagonist In vitro X4-tropic HIV infection [229,230] In vivo CXCR5 CXCL13 [231,232] CXCR6 CXCL16 [233,234] Small molecules with exo-[3.3.1] Antagonist In vitro G protein signaling [235] azabicyclononane core β-arrestin recruitment
In vivo Hepatocellular carcinoma CCR1 CCL2 In vitro G protein signaling [24,61] CCL3 β-arrestin recruitment CCL4 Receptor internalization CCL5 Chemotaxis CCL7 CCL8 CCL13 CCL14 CCL15 CCL16 CCL23 J113863 Antagonist In vitro Eosinophil morphology [236–239] UCB35625 Antagonist Receptor internalization Chemotaxis
In vivo Experimental murine arthritis Met-CCL5 (Met-RANTES) Antagonist In vitro Chemotaxis [240–242]
In vivo Experimental rat and murine arthritis Rabies virus CCX354 Antagonist In vitro Chemotaxis [243]
In vivo Inflammation Rheumatoid arthritis CP-481,715 Antagonist In vitro G protein signaling [244,245] Chemotaxis MLN3897 Antagonist In vivo Rheumatoid arthritis [246] BX471 Antagonist In vivo Multiple sclerosis [245] AZD-4818 Antagonist In vivo COPD [245] CCX9588 Antagonist In vitro Chemotaxis [247] LMD-559 Agonist In vitro G protein signaling [248] Chemotaxis CCR2 CCL2 G protein signaling [249] CCL7 β-arrestin recruitment CCL8 Receptor internalization CCL11 CCL13 CCL16 J113863 Agonist In vitro G protein signaling [169] UCB35625 Agonist β-arrestin recruitment Chemotaxis CAS 445479-97-0 Antagonist In vitro Cell proliferation [250] Cell migration Invasion INCB3344 Antagonist In vitro G protein signaling [251,252] β-arrestin recruitment Chemotaxis N-(2-((1-(4-(3-methoxyphenyl)cyclohexyl) Antagonist [253] piperidin-4-yl)amino)-2-oxoethyl)-3- (trifluoromethyl)benzamide (continued on next page)
10 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 (continued )
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
CCR2-RA Antagonist In vitro G protein signaling [252] β-arrestin recruitment 15a Antagonist In vivo Murine atherogenesis [254] MK-0812 Antagonist In vitro Cell morphology [255]
In vivo Monocyte recruitment CCR3 CCL5 In vitro G protein signaling [238,256] CCL7 Receptor internalization CCL8 Chemotaxis CCL11 CCL13 CCL15 CCL24 CCL26 CCL28 J113863 Antagonist In vitro Eosinophil morphologic change [236–238] UCB35625 Antagonist Receptor internalization CCR3-tropic HIV-1 infection Chemotaxis CH0076989 Agonist In vitro Eosinophil shape change [238] Receptor internalization Chemotaxis SB-328437 Antagonist In vitro G protein signaling [257] Eosinophil chemotaxis R321 Antagonist In vitro G protein signaling [258] β-arrestin recruitment Chemotaxis Receptor internalization
Eosinophil recruitment to lungs Murine airway hyperresponsiveness GW766994 Antagonist In vivo Asthma [259] Eosinophilic bronchitis CCR4 CCL17 In vitro G protein signaling [52,260–262] CCL22 β-arrestin recruitment Receptor internalization Chemotaxis
In vivo Inflammation MDC67 Antagonist In vitro G protein signaling [52] Compounds 1-4 Antagonist β-arrestin recruitment Receptor internalization Chemotaxis Compound 8a Antagonist In vitro Chemotaxis [263]
In vivo Allergic asthma in mice CCR5 CCL2 In vitro G protein signaling [24,242] CCL3 β-arrestin recruitment CCL3L1 Receptor internalization CCL4 CCL5 In vivo Inflammation CCL8 Rabies virus CCL11 CCL13 CCL14 CCL16 Maraviroc Antagonist In vivo R5-tropic HIV-1 infection [134] Aplaviroc Antagonist In vitro R5-tropic HIV-1 infection [264,265]
In vivo R5-tropic HIV-1 infection AOP-RANTES Agonist In vitro G protein signaling [160] Receptor internalization R5-tropic HIV-1 infection PSC-RANTES Super-agonist In vitro G protein signaling [162] 5P14-RANTES Receptor internalization 5P12-RANTES Agonist R5-tropic HIV-1 infection
Agonist TAK-652 Antagonist In vitro R5-tropic HIV-1 infection [266,267] TAK-779 Antagonist Vicriviroc Antagonist In vitro R5-tropic HIV-1 infection [268] In vivo In vitro [169] (continued on next page)
11 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 (continued )
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
J113863 Agonist G protein signaling UCB35625 Agonist β-arrestin recruitment Chemotaxis YM-370749 Agonist In vitro G protein signaling [269] β-arrestin recruitment Receptor internalization Chemotaxis R5-tropic HIV-1 infection Met-CCL5 (Met-RANTES) Antagonist In vitro Chemotaxis [240–242]
In vivo Experimental rat and murine arthritis Rabies virus SCH-351125 Antagonist In vitro G protein signaling [270–272] (Ancriviroc)
In vivo Rheumatoid arthritis E-913 Antagonist In vitro G protein signaling [270] CCR6 CCL20 In vitro Receptor Internalization [273–277] β-arrestin recruitment ERK phosphorylation Actin polymerization Graft-versus-host disease
In vivo Colorectal Cancer CCL20 S64C Agonist In vitro G protein signaling [278] β-arrestin recruitment Receptor internalization Chemotaxis
In vivo IL-23 dependent murine model of psoriasis CCR7 CCL19 In vitro G protein signaling [44,45,129,279] CCL21 β-arrestin recruitment Receptor internalization GRK engagement Chemotaxis β2 integrin activation
In vivo Naïve T cell recirculation in secondary lymphoid tissue Cmp2105 Allosteric antagonist In vitro Crystal structure [280] CS-1 Allosteric antagonist β-arrestin recruitment CS-2 Allosteric antagonist Thermal shift assay Navarixin Allosteric antagonist Cosalane Antagonist In vitro β-arrestin recruitment [281] Chemotaxis CCR8 CCL1 [282,283] CCL8 CCL16 CCL18 LMD-559 Agonist In vitro G protein signaling [248] Chemotaxis R243 Antagonist In vitro G protein signaling [284] Macrophage aggregation Cytokine secretion In vivo Hapten induced colitis Peritoneal adhesions Napthalene-sulfonamide derivatives Allosteric In vitro G protein signaling [285] antagonists Chemotaxis CCR9 CCL25 [286] Vercirnon Allosteric antagonist In vitro Crystal structure [108,287,288] G protein signaling
In vivo Crohn’s disease CCX8037 Antagonist In vitro Chemotaxis [289]
In vivo Intestinal T cell accumulation CCX282-B Antagonist In vitro G protein signaling [290,291] CCX025 Antagonist Chemotaxis
(continued on next page)
12 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
Table 1 (continued )
Receptor Endogenous Synthetic ligands Synthetic ligand System Assays References ligands characterization
Crohn’s disease In vivo Ulcerative colitis CCR10 CCL27 In vitro G protein signaling [24,292] CCL28 β-arrestin recruitment Receptor internalization Chemotaxis Eut-22 Antagonist In vitro G protein signaling [293] Chemotaxis
In vivo Murine contact hypersensitivity CX3CR1 CX3CL1 [294] JMS-17-2 Antagonist In vitro Chemotaxis [295,296] Pancreatic ductal adenocarcinoma motility and viability
In vivo Breast cancer metastasis KAND567 Antagonist In vivo Atherosclerosis [297] Myocardial infarction XCR1/ XCL1 [298] CCXCR1 XCL2 ACKR1/ CXCL5 [299] DARC CXCL6 CXCL8 CXCL11 CCL2 CCL5 CCL7 CCL11 CCL13 CCL14 CCL17 ACKR2 CCL2 In vitro G protein signaling [300,301] CCL3 Receptor internalization CCL4 CCL5 CCL7 CCL8 CCL11 CCL13 CCL14 CCL17 CCL22 CCL14 [9–74] Agonist In vitro G protein signaling [300,301] Actin rearrangement Receptor internalization ACKR3/ CXCL11 In vitro G protein signaling [62,63,66,299] CXCR7 CXCL12 β-arrestin recruitment Chemotaxis TC14012 Allosteric antagonist In vitro β-arrestin recruitment [302] GSLW Allosteric agonist In vitro β-arrestin recruitment [303] Receptor internalization FC313 Allosteric agonist In vitro β-arrestin recruitment [304] CXCL11_12 chimera Agonist In vitro Selective ACKR3 agonist, over [305,306] CXCR3 and CXCR4 AMD3100 Allosteric agonist In vitro β-arrestin recruitment [307] VUF11207 Agonist In vitro β-arrestin recruitment [308] VUF11403 Receptor internalization CCX771 Agonist In vitro β-arrestin recruitment [309–312] Receptor internalization Chemotaxis Trans-endothelial migration In vivo Tumor growth Tumor growth and metastasis Tumor angiogenesis X4-tropic HIV-1 infection CCX777 Agonist In vitro β-arrestin recruitment [86] ACKR4/ CCL19 ` [299,313] CCR11 CCL20 CCL21 CCL25
13 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
CXCL9 and CXCL10 [89,116]. Synthetic small molecule agonists, endogenous ligand or exceeding optimal levels for chemotaxis by VUF10661 and VUF11418, similarly display biased agonism at CXCR3, nullifying endogenous CXCL12 gradients produced in distant tissues with VUF10661 characterized as β-arrestin-biased and VUF11418 as G [122–124]. Drury et al. demonstrate that the monomeric form of protein-biased [116,117]. Notably, Smith et al. showed in a murine CXCL12 is much more efficacious in stimulating filamentous-actin model of allergic contact hypersensitivity that VUF10661 potentiates a polymerization and inducing chemotaxis than the dimeric form [55]. dinitrofluorobenzene-inducedinflammatory response, while VUF11418 From this in vitro evidence, one could postulate that the dimeric form of does not [116]. This increase in inflammation derived from VUF10661 CXCL12 would inhibit metastasis and the monomeric form would pro was lost when these experiments were repeated in β-arrestin 2 knock out mote metastasis. However, the authors found that exogenous adminis + (KO) mice. Additionally, a greater number of CD3 T cells and, specif tration of either WT CXCL12, a preferentially monomeric form, or + + + ically, CD3 β-arrestin CXCR3 T cells, were found in tissue biopsies preferentially dimeric form all inhibited tumor metastasis to similar derived from patients with allergic contact dermatitis than from non extents. The reasons underlying this discrepancy between in vitro and in lesional controls. However, in vitro chemotaxis assays further revealed vivo work is possibly due to systems bias where the function of exoge that both β-arrestin dependent phosphorylation of Akt and G protein nously administered CXCL12 may assume a different function in vivo. signaling contribute to CXCR3-mediated chemotaxis [116]. The exact Furthermore, CXCR4 also exhibits receptor bias in WHIM syndrome consequences of G protein and β-arrestin bias for chemotaxis are which is most commonly due to a gain of function receptor C terminal therefore still unclear. While VUF10661 induces the greatest chemo truncation mutant [125]. The truncated CXCR4 receptor found in these tactic response, G protein signaling is additionally necessary for any patients promotes more G protein dependent signaling cascades chemotactic response, as T cell migration controlled by CXCL9, CXCL10, compared to the WT receptor, presumably due to the decreased ability to and CXCL11 is abrogated following pretreatment with pertussis toxin, recruit the GRKs and β-arrestins and desensitize the receptor. However, an inhibitor of Gαi [116,118]. It is possible that β-arrestin and G protein there is evidence demonstrating that, even in this truncated receptor, dependent signaling cascades that contribute to the overall chemotactic β-arrestin is still able to engage the receptor via intracellular loop 3 and response are interrelated. that β-arrestins engage in different signaling cascades than those in the Biased signaling at CXCR3 has also been found to direct T cell po WT receptor. Lagane et al. demonstrate using CXCR4 mutants derived larization and function [119]. In a murine model of EAE, Zohar et al. from patients with WHIM syndrome that receptor desensitization and found that CXCL10 induces polarization of T helper (Th) cells into Th1/ internalization is regulated by the C terminal tail of CXCR4 while Th17 cells, promoting inflammation, whereas CXCL11 promotes Th β-arrestin-mediated signaling, like ERK1/2 activation, is primarily polarization into IL-10-producing T regulatory (Treg) cells, dampening mediated by its interaction with ICL3 [125]. The authors also show that inflammation. The authors also demonstrate distinct downstream WT CXCR4 can homodimerize and also heterodimerize with mutant signaling cascades for the endogenous ligands, with induction of T cell CXCR4 receptors; these heterodimers are able to further enhance polarization by CXCL10 via phosphorylation of STAT1, STAT4, and chemotaxis due to reduced internalization of both the mutant and WT STAT5, and by CXCL11 via phosphorylation of STAT3 and STAT6 [120]. CXCR4 and prolonged β-arrestin dependent signaling as measured by Additionally, CXCR3 signaling directs T cell localization by limiting Th ERK 1/2 phosphorylation [125]. This study highlights the many com cells to the perivascular space in the central nervous system, thereby plex levels of bias that can exist in the chemokine system, where a biased increasing interaction between Treg and Th cells, and attenuating receptor can not only direct different signaling patterns, but influence inflammation,demyelination, and axonal damage [121]. CXCR3-/- mice those of wild-type receptors. Studies have also shown, among others, demonstrate a more disorganized perivascular distribution of Th cells CCR5 homodimerization shortly after synthesis in the endoplasmic re and experience increased tissue damage and less recovery in EAE than ticulum, CXCR4 homodimer formation and heterodimer formation with WT CXCR3 mice [121]. Biased signaling has not been directly impli CCR2, and CXCR2 homodimerization [126–128]. Future research in this cated in this disease process; however, there is evidence demonstrating area could uncover unidentifiedsources of biased signaling, which could that in murine EAE, CXCL9, CXCL10, and CXCL11 are expressed in explain many of the non-redundant functional effects seen within the different spatial and cellular locations within the central nervous sys chemokine system. tem, suggesting a functional role of biased agonism at CXCR3 [121]. 5.4. CCR7 5.2. CXCR1 and CXCR2 There is evidence of biased agonism at CCR7 between its endogenous There is also evidence demonstrating different cellular signaling ligands CCL19 and CCL21 and their role in lymphocyte extravasation induced by CXCL8 at its endogenous receptors, CXCR1 and CXCR2, both and lymphocyte trafficking to and within secondary lymphoid organs of which are primarily involved in directing neutrophil chemotaxis to [45,129]. Forster¨ et al. demonstrated the importance of CCR7 in these sites of infection and initiating its cytotoxic effects [56]. Interestingly, signaling pathways by generating CCR7 deficient mice, which had CXCL8 can exist as a monomer, dimer, or a combination of these two impaired entry and retention of naïve T cells, dendritic cells (DCs), and B states in vivo. Nasser et al. provide evidence for biased signaling in this cells in multiple secondary lymphoid organs [129]. CCR7-dependent system in that the monomeric form of CXCL8 is more effective at driving signaling is therefore likely necessary for effective T cell-B cell and T calcium mobilization, chemotaxis and exocytosis than the dimeric form. cell-DC interactions. They also discovered that this ligand bias is present at CXCR1, but not at Kohout et al. further characterize biased signaling at CCR7 by CXCR2, suggesting an interaction between both ligand and receptor examining receptor desensitization and ERK1/2 activation in response bias. To our knowledge, the functional consequences of this ligand and to CCL19 and CCL21 [45]. The endogenous ligands promote nearly receptor bias have not been rigorously explored in vivo. identical amounts of G protein signaling, but only CCL19 induces sub stantial receptor desensitization via receptor C terminal phosphoryla 5.3. CXCR4 tion and β-arrestin recruitment [45]. Although these ligands induce similar calcium mobilization and leukocyte migration potential in vitro, Similarly, at CXCR4, which is implicated in tumor cell trafficking, CCL19, but not CCL21, induces rapid CCR7 internalization [130]. differential signaling by the monomeric and dimeric forms of its Resultingly, pretreatment of T lymphocytes with CCL19 inhibits a endogenous ligand CXCL12 demonstrated functional consequences in a chemotactic response to either CCL19 or CCL21, while cells retain full murine model of colorectal carcinoma or melanoma [55]. Previous chemotactic potential following pretreatment with CCL21 [130]. research has shown that locally produced CXCL12 limits migration po When comparing CCL19-/- mice, plt/plt mice (deficient in both tential of cells expressing CXCR4 by either desensitizing these cells to CCL19 and CCL21), and plt/CCL19- mice (lacking CCL19 and one CCL21
14 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 allele) to WT mice, Britschgi et al. found that deficiency of both CCL19 tolerability [146]. Continued studies will determine whether these drugs and CCL21 is required for abnormal localization of DCs in lymph nodes represent promise for therapeutic benefit in their respective disease [131]. Interestingly, they also discovered that CCL19 was not needed for states. DC migration, maturation, and T-cell priming [131]. These results suggest that CCL19 is dispensable for certain aspects of DC function 6.1. CCR5 in HIV regulated by CCR7. It is unclear if CCL19 is sufficientto support normal DC function in the absence of CCL21, and if CCL19 and CCL21 have both A large component of drug development in the chemokine system overlapping and distinct physiologic roles. Taken together, these studies has been focused on inhibition of HIV-1 entry and infection. R5-tropic indicate the importance of biased signaling at CCR7 in the traffickingof HIV-1, the predominant form of the virus during initial transmission a wide array of immune cells, as well as their interactions within sec and infection, requires CCR5 as a co-receptor to CD4 for entry into ondary lymphoid tissues. monocytes and macrophages [147–151]. X4-tropic virus, which appears later and is responsible for the serious reduction in Th cell count, re 6. Targeting Chemokine System Biased Agonism in Drug quires CXCR4 as a co-receptor to CD4 [147–151]. A surge in research on Development chemokine receptor biology occurred following the findings that CCR5Δ32 homozygous mutant individuals are resistant to HIV infection, As opposed to the other GPCRs that have one or perhaps a few and CCR5Δ32 heterozygous mutant individuals had a slower progres endogenous ligands, most CKRs have a number of endogenous ligands, sion to AIDS after infection [152–156]. These small populations of in many of which are biased, have additional receptor targets, and have dividuals have truncated forms of CCR5 that fail to reach the cell surface variable tissue expression. This primary example of naturally occurring and, therefore, cannot be utilized by HIV to enter the cell. This led to the biased agonism may unveil a variety of new drug targets which exploit development of maraviroc, a CCR5 antagonist which is currently used this biochemical phenomenon, but it may also uncover key information for combination antiretroviral therapy in adults infected with R5-tropic regarding the mechanisms and structural determinants underlying HIV-1 [157,158]. Drugs which induce receptor internalization of CCR5 biased agonism across all GPCRs. An enhanced understanding of the or CXCR4, a canonically β-arrestin driven process, may therefore pro mechanisms that control biased signaling in GPCRs may lead to the vide significanttherapeutic benefit.Interestingly, while there have been development of pharmaceutical drugs with increased efficacy and worries that such a pharmacological approach would lead to deleterious reduced side effect profileby selectively activating therapeutic signaling immunological side effects, CCR5Δ32 mutant individuals do not appear pathways. Biased therapeutics at other GPCR subtypes, including the to be immunocompromised [159]. However, this finding does not sug type 1 angiotensin II receptor (AT1R), μ-opioid receptor, κ-opioid re gest that a drug of this type would not have serious side effect, and future ceptor, D2 dopamine receptor have demonstrated that differential research should rigorously study these details to determine if this is a activation of G-protein and β-arrestin signaling pathways has the po viable therapeutic strategy. tential to improve efficacy and avoid unwanted side effects. However, While endogenous CCR5 ligands CCL3, CCL4, and CCL5 (RANTES) the in vivo effects of these compounds can be difficult to predict, even and CCL8 display limited degrees of bias [43], many modified chemo with detailed studies involving knockout animals and comparisons to kine analogs for CCR5 do exhibit a high degree of bias. AOP-RANTES is balanced agonists and antagonists. β-arrestin-biased agonist, which rapidly induces CCR5 internalization, Due to the wide range of biological processes and pathologies in and inhibits recycling to the cell surface, retaining a large amount of which the chemokine system is implicated, identificationof biased drugs receptor in endosomes [160]. Notably, it has been shown that the po targeting chemokine ligands and receptors is of significant interest in tency of AOP-RANTES and CCL5 to inhibit R5-tropic HIV-1 infection was clinical research. Yet, the success of drug development to target the correlated with the degree of CCR5 internalization and inhibition of chemokine system and its associated pathologies has been limited. recycling, which supports the notion that these processes represent Although clinical trials over the past decade have attempted to target therapeutic targets to prevent HIV-1 infection [160]. Unfortunately, over 50% of CKRs [132], there are currently only three FDA approved AOP-RANTES simultaneously promoted the intracellular replication of drugs on the market that target CKRs. Maraviroc is a CCR5 antagonist HIV-1 via a mechanism downstream of viral entry that is sensitive to that inhibits R5-tropic HIV-1 entry into cells [133,134]. Plerixafor pertussis toxin, suggesting a role for the Gαi subunit in viral replication (AMD3100) is a CXCR4 antagonist first identified to block X4-tropic [161]. PSC-RANTES, is a balanced CCR5 super-agonist that is 50 times HIV-1 infection, but is now FDA-approved for use in autologous he more potent than AOP-RANTES for HIV infection inhibition in vitro and matopoietic stem cell (HSC) transplantation in patient with Non-Hodg acts via a mechanism of long-term intracellular sequestration of CCR5 kin’s lymphoma or multiple myeloma [135–138]. CXCR4 signaling [162]. While PSC-RANTES serves as a potential topical agent to prevent promotes the retention of HSCs in the bone marrow and AMD3100, as an HIV transmission at mucosal barriers, CCR5 induced receptor internal antagonist of CXCR4, mobilizes HSCs into the peripheral blood, a crucial ization occurs alongside other CCR5 direct signaling pathways which step for conferring the therapeutic benefitof autologous transplantation have been shown to result in intense mucosal inflammation and para [139]. Finally, mogamulizumab is a CCR4 antibody used for treating doxically enhance HIV infection [163]. 5P14-RANTES is a β-arrestin- cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lym biased agonist that induces no detectable G protein activation but does phoma (ATLL) [140,141]. Currently, phase 3 clinical trials are under induce receptor internalization, however, not to the extent of PSC- way to evaluate additional chemokine antagonists including the CCR5 RANTES. PSC-RANTES and 5P14-RANTES also differ in their post- antagonist leronimab and CXCR4 antagonists balixafortide and mavor endocytic trafficking of CCR5, a spatiotemporal form of bias that ixafor [142]. Studies for leronimab are investigating the safety and could have significant implications for their ability to inhibit HIV effectiveness of using it with and without an optimized antiretroviral infection [164]. PSC-RANTES directs internalized receptor firstinto the therapy (ART) regimen and for the safety and effectiveness of leronimab endosome recycling compartment (ERC) and then into the trans-Golgi monotherapy for the maintenance of R5-tropic HIV-1 suppression over network (TGN), resulting in long term sequestration, while 5P14- 48 weeks [143,144]. Balixafortide is currently being studied for its ef RANTES directs CCR5 only to the ERC, resulting in short term seques ficacy,safety and tolerability when given intravenously with eribulin, a tration [164]. Bonsch¨ et al. suggest that duration of β-arrestin associa common breast cancer chemotherapy drug, versus eribulin alone in the tion with CCR5 is key to the differential post-endocytic receptor treatment of HER2 negative, locally recurrent or metastatic breast trafficking,with PSC-RANTES inducing robust and long-term β-arrestin cancer [145]. Mavorixafor is being examined for its efficacy in partici recruitment to CCR5 and 5P14-RANTES inducing recruitment that is pants with WHIM syndrome as assessed by increasing levels of circu more transient in nature [164]. lating neutrophils compared with placebo, as well as its safety and Altogether, the past roughly 20 years of research on the importance
15 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862 of CCR5 and CXCR4 for HIV entry and infection of leukocytes reveals a creating a biased signaling profile that demonstrates decreased drug pathological state in which biased signaling could provide significant tolerance [168]. These findingssuggest the potential of biased allosteric therapeutic benefit.However, it is still not clear exactly to what extent G modulators to provide therapeutic benefit to patients who develop protein signaling and β-arrestin recruitment, and their associated tolerance to unbiased antagonists. At CCR2 and CCR5, synthetic enan downstream signaling cascades affect HIV entry and infection. Addi tiomers J113863 and UCB35625 exhibit differential G protein signaling tionally, the side effect profiles of synthetic ligands which induce re and β-arrestin recruitment, as well as functional effects on L1.2 cell (a ceptor internalization have not been determined, an important question mouse leukemia cell line) chemotaxis [169]. This represents the first for future research to address in order to develop clinically efficacious description of chemokine receptor ligands displaying enantioselective drugs. properties, a finding of particular pharmacologic significance as many drugs are typically racemic mixtures [169]. 6.2. CXCR3 and T cell-mediated inflammation 7. Conclusion Similar efforts to target the biased signaling properties of the che mokine system have been focused on CXCR3. CXCR3 is an important The discovery of alternative signaling pathways beyond G protein mediator of Th1 cell function and plays a role in natural killer cell signaling, specificallythose driven by β-arrestin, have led to a renewed migration and inhibition of angiogenesis [165]. CXCR3 is rapidly appreciation of the complexity and non-redundant nature of the che expressed on naïve T cells following their activation and remains highly mokine system. The number of possible cellular phenotypes driven by + + expressed on Th1-type CD4 T cells and effector CD8 T cells [166]. the chemokine signaling are staggering when considering the diversity CXCR3, regulated by its three interferon-inducible endogenous ligands, of ligands, receptors, and cell and tissue types implicated in this system. CXCL9, CXCL10, and CXCL11, promotes T cell trafficking to peripheral Rather than being designed to simply produce robust outputs, numerous sites of inflammation, as well as lymphoid tissues, facilitating the functional and structural studies suggest that the chemokine system is interaction of T cells with antigen presenting cells [166]. CXCR3 and its capable of driving highly specific and directed signaling processes to endogenous ligands have been implicated in a variety of disease pro coordinate immune cell function. Considering that CKRs are found in cesses and pathological states, including allergic contact dermatitis, many non-immune related tissue types, the complexity of the biased autoinflammation and autoimmunity, atherosclerosis, and cancer signaling within this system is likely underappreciated. An enhanced metastasis [116,167]. As previously mentioned, Smith et al. demon understanding of the pluridimensional efficacy within the chemokine strate the pharmacologic potential of biased signaling at CXCR3 using a system presents an opportunity to determine the fundamental principles mouse model of allergic contact hypersensitivity [116]. Their finding underlying biased agonism across all GPCRs. Additionally, the phe that both G protein signaling and β-arrestin-mediated signaling are nomenon of biased signaling within the chemokine system presents a necessary for full chemotactic function suggests that drugs designed to potential target for future drug development. Within the complex + increase migration of CXCR3 T cells, such as those used in cancer signaling mechanisms of the chemokine system lies the potential for immunotherapy, could promote signaling through the β-arrestin, Gαi, or greater druggability, with more focused pharmacological effects and potentially both [116]. On the other hand, a more complicated picture possibly fewer harmful side effects. Although biased agonism has been + arises for development of drugs designed to inhibit migration of CXCR3 widely observed using both endogenous and synthetic chemokine li T cells to reduce inflammation [116]. Pertussis toxin treatment gands, understanding the mechanisms and functional effects of this completely abrogates T cell chemotaxis, whereas Akt inhibition and complex signaling in vivo must progress in order to develop promising β-arrestin 2 knock out (KO) T cells display only reduced chemotaxis therapeutics. Many of the problems faced in pharmaceutical research on [116]. Therefore, further research is needed to determine the most chemokine-targeted therapeutics relate to an apparent lack of trans efficaciousmechanism of action for drugs designed to promote or inhibit lation between cellular, animal, and human models, as well as an + migration of CXCR3 T cells. Karin et al. suggest the possibility of using incomplete understanding of the biochemical and physiological impli stabilized chemokines as biological drugs for autoimmunity and graft- cations of the chemokine system bias. Advances in our understanding of versus-host disease (GVHD) [119]. Endogenous chemokines have rela the structural and functional determinants of biased agonism may be tively short half-lives, and therefore their administration alone does not necessary before the promise of more effective therapeutics aimed at provide significant therapeutic benefit. Based on their finding that treating CKR- and GPCR-related pathologies can be fully realized. CXCL11 induces T cell polarization toward IL-10-producing Treg cells, whereas CXCL9 and CXCL10 induce T cell polarization toward Th1/ CRediT authorship contribution statement Th17 cells, Karin et al. propose that exogenously stabilized chemokines could be developed as biological drugs at CXCR3 that selectively acti Dylan Scott Eiger: Conceptualization, Writing - original draft, + vate FOXP3 Treg or Tr1 cells over proinflammatory cells, taking Writing - review & editing. Noelia Boldizsar: Writing - original draft, advantage of the phenomenon of biased agonism [119]. Writing - review & editing. Christopher Cole Honeycutt: Writing - original draft, Writing - review & editing. Julia Gardner: Writing - 6.3. Other CKRs original draft, Writing - review & editing. Sudarshan Rajagopal: Writing - original draft, Writing - review & editing. Lastly, the pharmacologic potential of biased signaling has been implicated at various other CKRs. At CXCR4, drug tolerance has been Declaration of Competing Interest seen to occur in response to administration of AMD3100, with increasing CXCR4 expression on the surface of hematopoietic stem cells None (HSCs), promoting their rehoming to the bone marrow [168]. Hitch inson et al. found that such drug tolerance was avoided in vitro with Acknowledgements administration of X4-2-6, a β-arrestin-biased peptide antagonist [168]. X4-2-6 forms a ternary complex with endogenous CXCL12 and CXCR4, This work was supported by the National Institute of General Med causing the N terminus of CXCL12 to detach from CXCR4. This N ter ical Sciences T32GM00717 (D.S.E) and R01GM122798 (S.R); the Duke minal interaction is important for inducing the conformational change University Medical Scientist Training Program (D.S.E); and the Amer in CXCR4 that promotes GTP loading of Gαi, and X4-2-6 therefore in ican Heart Association Predoctoral Fellowship 20PRE35120592 (D.S.E). hibits G protein signaling [168]. Receptor C terminal phosphorylation, β-arrestin recruitment, and receptor internalization are retained,
16 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
References [34] J.S. Smith, S. Rajagopal, The beta-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors, J Biol Chem. 291 (17) (2016) 8969–8977. [35] J.D. Violin, R.J. Lefkowitz, Beta-arrestin-biased ligands at seven-transmembrane [1] D. Rossi, A. Zlotnik, The Biology of Chemokines and their Receptors, Annual receptors, Trends Pharmacol Sci. 28 (8) (2007) 416–422. Review of Immunology. 18 (1) (2000) 217–242. [36] van Gastel J, Hendrickx JO, Leysen H, Santos-Otte P, Luttrell LM, Martin B, et al. [2] D.J. Scholten, M. Canals, D. Maussang, L. Roumen, M.J. Smit, M. Wijtmans, et al., beta-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets Pharmacological modulation of chemokine receptor function, Br J Pharmacol. for Complex Age-Related Disorders. Front Pharmacol. 2018;9:1369. 165 (6) (2012) 1617–1643. [37] R.J. Lefkowitz, K. Rajagopal, E.J. Whalen, New roles for beta-arrestins in cell [3] S.J. Allen, S.E. Crown, T.M. Handel, Chemokine: receptor structure, interactions, signaling: not just for seven-transmembrane receptors, Mol Cell. 24 (5) (2006) and antagonism, Annu Rev Immunol. 25 (2007) 787–820. 643–652. [4] A. Zlotnik, A.M. Burkhardt, B. Homey, Homeostatic chemokine receptors and [38] S.M. DeWire, S. Ahn, R.J. Lefkowitz, S.K. Shenoy, Beta-arrestins and cell organ-specific metastasis, Nat Rev Immunol. 11 (9) (2011) 597–606. signaling, Annu Rev Physiol. 69 (2007) 483–510. [5] L. Rajagopalan, K. Rajarathnam, Structural basis of chemokine receptor function– [39] J.S. Smith, R.J. Lefkowitz, S. Rajagopal, Biased signalling: from simple switches to a model for binding affinity and ligand selectivity, Biosci Rep. 26 (5) (2006) allosteric microprocessors, Nat Rev Drug Discov. 17 (4) (2018) 243–260. 325–339. [40] M. Liebick, S. Henze, V. Vogt, M. Oppermann, Functional consequences of [6] C.E. Hughes, R.J.B. Nibbs, A guide to chemokines and their receptors, FEBS J. chemically-induced beta-arrestin binding to chemokine receptors CXCR4 and 285 (16) (2018) 2944–2971. CCR5 in the absence of ligand stimulation, Cell Signal. 38 (2017) 201–211. [7] R.C. Russo, C.C. Garcia, M.M. Teixeira, Anti-inflammatory drug development: [41] S. Galandrin, M. Bouvier, Distinct signaling profilesof beta1 and beta2 adrenergic Broad or specificchemokine receptor antagonists? Curr Opin Drug Discov Devel. receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase 13 (4) (2010) 414–427. reveals the pluridimensionality of efficacy, Mol Pharmacol. 70 (5) (2006) [8] M.M. Rosenkilde, T.W. Schwartz, The chemokine system – a major regulator of 1575–1584. angiogenesis in health and disease, APMIS. 112 (7–8) (2004) 481–495. [42] T. Kenakin, Agonist-receptor efficacy. II. Agonist trafficking of receptor signals, [9] W. Rost`ene, P. Kitabgi, S.M. Parsadaniantz, Chemokines: a new class of Trends Pharmacol Sci. 16 (7) (1995) 232–238. neuromodulator? Nature Reviews Neuroscience. 8 (11) (2007) 895–903. [43] J. Corbisier, C. Gales,` A. Huszagh, M. Parmentier, J.Y. Springael, Biased signaling [10] Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring at chemokine receptors, J Biol Chem. 290 (15) (2015) 9542–9554. Harb Perspect Biol. 2015;7(5). [44] D.A. Zidar, J.D. Violin, E.J. Whalen, R.J. Lefkowitz, Selective engagement of G [11] Y.R. Cha, M. Fujita, M. Butler, S. Isogai, E. Kochhan, A.F. Siekmann, et al., protein coupled receptor kinases (GRKs) encodes distinct functions of biased Chemokine signaling directs trunk lymphatic network formation along the ligands, Proc Natl Acad Sci U S A. 106 (24) (2009) 9649–9654. preexisting blood vasculature, Dev Cell. 22 (4) (2012) 824–836. [45] T.A. Kohout, S.L. Nicholas, S.J. Perry, G. Reinhart, S. Junger, R.S. Struthers, [12] O. Meucci, A. Fatatis, A.A. Simen, T.J. Bushell, P.W. Gray, R.J. Miller, Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity, and ERK1/2 activation by the two endogenous ligands for the CC chemokine Proc Natl Acad Sci U S A. 95 (24) (1998) 14500–14505. receptor 7, J Biol Chem. 279 (22) (2004) 23214–23222. [13] A.H. de Haas, H.R. van Weering, E.K. de Jong, H.W. Boddeke, K.P. Biber, [46] M.A. Byers, P.A. Calloway, L. Shannon, H.D. Cunningham, S. Smith, F. Li, et al., Neuronal chemokines: versatile messengers in central nervous system cell Arrestin 3 mediates endocytosis of CCR7 following ligation of CCL19 but not interaction, Mol Neurobiol. 36 (2) (2007) 137–151. CCL21, J Immunol. 181 (7) (2008) 4723–4732. [14] Z. Wang, H. Shang, Y. Jiang, Chemokines and Chemokine Receptors: Accomplices [47] J.S. Smith, P. Alagesan, N.K. Desai, T.F. Pack, J.H. Wu, A. Inoue, et al., C-X-C for Human Immunodeficiency Virus Infection and Latency, Front Immunol. 8 Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins (2017) 1274. to Regulate Downstream Signaling Pathways, Mol Pharmacol. 92 (2) (2017) [15] J.S. Smith, S. Rajagopal, A.R. Atwater, Chemokine Signaling in Allergic Contact 136–150. Dermatitis: Toward Targeted Therapies, Dermatitis. 29 (4) (2018) 179–186. [48] Y.A. Berchiche, S. Gravel, M.E. Pelletier, G. St-Onge, N. Heveker, Different effects [16] F.R. Balkwill, The chemokine system and cancer, J Pathol. 226 (2) (2012) of the different natural CC chemokine receptor 2b ligands on beta-arrestin 148–157. recruitment, Gαi signaling, and receptor internalization, Mol Pharmacol. 79 (3) [17] Antonia AL, Gibbs KD, Trahair ED, Pittman KJ, Martin AT, Schott BH, et al. (2011) 488–498. Pathogen Evasion of Chemokine Response Through Suppression of CXCL10. [49] A.O. Watts, D.J. Scholten, L.H. Heitman, H.F. Vischer, R. Leurs, Label-free Frontiers in Cellular and Infection Microbiology. 2019;9(280). impedance responses of endogenous and synthetic chemokine receptor CXCR3 [18] A. Zernecke, C. Weber, Chemokines in Atherosclerosis, Arteriosclerosis, agonists correlate with Gi-protein pathway activation, Biochem Biophys Res Thrombosis, and Vascular Biology. 34 (4) (2014) 742–750. Commun. 419 (2) (2012) 412–418. [19] P.J. Koelink, S.A. Overbeek, S. Braber, P. de Kruijf, G. Folkerts, M.J. Smit, et al., [50] G. O’Boyle, J.G. Brain, J.A. Kirby, S. Ali, Chemokine-mediated inflammation: Targeting chemokine receptors in chronic inflammatory diseases: an extensive Identificationof a possible regulatory role for CCR2, Mol Immunol. 44 (8) (2007) review, Pharmacol Ther. 133 (1) (2012) 1–18. 1944–1953. [20] P.A. Hernandez, R.J. Gorlin, J.N. Lukens, S. Taniuchi, J. Bohinjec, F. Francois, et [51] J. Sanchez, J.R. Lane, M. Canals, M.J. Stone, Influenceof Chemokine N-Terminal al., Mutations in the chemokine receptor gene CXCR4 are associated with WHIM Modificationon Biased Agonism at the Chemokine Receptor CCR1, Int J Mol Sci. syndrome, a combined immunodeficiency disease, Nat Genet. 34 (1) (2003) 20 (2019) 10. 70–74. [52] L. Ajram, M. Begg, R. Slack, J. Cryan, D. Hall, S. Hodgson, et al., Internalization of [21] A.B. Kleist, A.E. Getschman, J.J. Ziarek, A.M. Nevins, P.A. Gauthier, A. Chevigne,´ the chemokine receptor CCR4 can be evoked by orthosteric and allosteric et al., New paradigms in chemokine receptor signal transduction: Moving beyond receptor antagonists, Eur J Pharmacol. 729 (2014) 75–85. the two-site model, Biochem Pharmacol. 114 (2016) 53–68. [53] J.P. Ludeman, M.J. Stone, The structural role of receptor tyrosine sulfation in [22] A. Mantovani, The chemokine system: redundancy for robust outputs, Immunol chemokine recognition, Br J Pharmacol. 171 (5) (2014) 1167–1179. Today. 20 (6) (1999) 254–257. [54] A.E.I. Proudfoot, Z. Johnson, P. Bonvin, T.M. Handel, Glycosaminoglycan [23] M.N. Devalaraja, A. Richmond, Multiple chemotactic factors: fine control or Interactions with Chemokines Add Complexity to a Complex System, redundancy? Trends Pharmacol Sci. 20 (4) (1999) 151–156. Pharmaceuticals (Basel). 10 (3) (2017). [24] S. Rajagopal, D.L. Bassoni, J.J. Campbell, N.P. Gerard, C. Gerard, T.S. Wehrman, [55] L.J. Drury, J.J. Ziarek, S. Gravel, C.T. Veldkamp, T. Takekoshi, S.T. Hwang, et al., Biased agonism as a mechanism for differential signaling by chemokine receptors, Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 J Biol Chem. 288 (49) (2013) 35039–35048. interactions and signaling pathways, Proc Natl Acad Sci U S A. 108 (43) (2011) [25] K.L. Pierce, R.T. Premont, R.J. Lefkowitz, Seven-transmembrane receptors, Nat 17655–17660. Rev Mol Cell Biol. 3 (9) (2002) 639–650. [56] M.W. Nasser, S.K. Raghuwanshi, D.J. Grant, V.R. Jala, K. Rajarathnam, R. [26] A.S. Hauser, M.M. Attwood, M. Rask-Andersen, H.B. Schioth, D.E. Gloriam, M. Richardson, Differential activation and regulation of CXCR1 and CXCR2 by Trends in GPCR drug discovery: new agents, targets and indications, Nat Rev CXCL8 monomer and dimer, J Immunol. 183 (5) (2009) 3425–3432. Drug Discov. 16 (12) (2017) 829–842. [57] J.J. Ziarek, A.B. Kleist, N. London, B. Raveh, N. Montpas, J. Bonneterre, et al., [27] S. Rajagopal, K. Rajagopal, R.J. Lefkowitz, Teaching old receptors new tricks: Structural basis for chemokine recognition by a G protein-coupled receptor and biasing seven-transmembrane receptors, Nat Rev Drug Discov. 9 (5) (2010) implications for receptor activation, Sci Signal. 10 (471) (2017). 373–386. [58] C.T. Veldkamp, C. Seibert, F.C. Peterson, N.B. De la Cruz, J.C. Haugner, H. Basnet, [28] S.R. Neves, P.T. Ram, R. Iyengar, G Protein Pathways, Science. 296 (5573) (2002) et al., Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF- 1636–1639. 1/CXCL12, Sci Signal. 1 (37) (2008) ra4. [29] A. Steen, O. Larsen, S. Thiele, M.M. Rosenkilde, Biased and g protein-independent [59] A. Mortier, M. Gouwy, J. Van Damme, P. Proost, Effect of posttranslational signaling of chemokine receptors, Front Immunol. 5 (2014) 277. processing on the in vitro and in vivo activity of chemokines, Exp Cell Res. 317 [30] E. Reiter, R.J. Lefkowitz, GRKs and beta-arrestins: roles in receptor silencing, (5) (2011) 642–654. trafficking and signaling, Trends Endocrinol Metab. 17 (4) (2006) 159–165. [60] E. Lorenzen, E. Ceraudo, Y.A. Berchiche, C.A. Rico, A. Furstenberg, T.P. Sakmar, [31] Legler DF, Thelen M. New insights in chemokine signaling. F1000Res. 2018;7:95. et al., G protein subtype-specific signaling bias in a series of CCR5 chemokine [32] H. Arai, C.L. Tsou, I.F. Charo, Chemotaxis in a lymphocyte cell line transfected analogs, Sci Signal. 11 (2018) 552. with C-C chemokine receptor 2B: evidence that directed migration is mediated by [61] Y. Tian, D.C. New, L.Y. Yung, R.A. Allen, P.M. Slocombe, B.M. Twomey, et al., betagamma dimers released by activation of Galphai-coupled receptors, Proc Natl Differential chemokine activation of CC chemokine receptor 1-regulated Acad Sci U S A. 94 (26) (1997) 14495–14499. pathways: ligand selective activation of Galpha 14-coupled pathways, Eur J [33] M. Lohse, J. Benovic, J. Codina, M. Caron, R. Lefkowitz, beta-Arrestin: a protein Immunol. 34 (3) (2004) 785–795. that regulates beta-adrenergic receptor function, Science. 248 (4962) (1990) 1547–1550.
17 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
[62] J.M. Burns, B.C. Summers, Y. Wang, A. Melikian, R. Berahovich, Z. Miao, et al., cell alpha chemoattractant are allotopic ligands for human CXCR3: differential A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell binding to receptor states, Mol Pharmacol. 59 (4) (2001) 707–715. adhesion, and tumor development, J Exp Med. 203 (9) (2006) 2201–2213. [89] R.A. Colvin, G.S. Campanella, L.A. Manice, A.D. Luster, CXCR3 requires tyrosine [63] K. Balabanian, B. Lagane, S. Infantino, K.Y. Chow, J. Harriague, B. Moepps, et al., sulfation for ligand binding and a second extracellular loop arginine residue for The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor ligand-induced chemotaxis, Mol Cell Biol. 26 (15) (2006) 5838–5849. RDC1 in T lymphocytes, J Biol Chem. 280 (42) (2005) 35760–35766. [90] A. Jaracz-Ros, G. Bernadat, P. Cutolo, C. Gallego, M. Gustavsson, E. Cecon, et al., [64] A. Levoye, K. Balabanian, F. Baleux, F. Bachelerie, B. Lagane, CXCR7 Differential activity and selectivity of N-terminal modifiedCXCL12 chemokines at heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling, the CXCR4 and ACKR3 receptors, J Leukoc Biol. 107 (6) (2020) 1123–1135. Blood. 113 (24) (2009) 6085–6093. [91] M. Szpakowska, A.M. Nevins, M. Meyrath, D. Rhainds, T. D’huys, F. Guit´e-Vinet, [65] F.M. Decaillot,´ M.A. Kazmi, Y. Lin, S. Ray-Saha, T.P. Sakmar, P. Sachdev, CXCR7/ et al., Different contributions of chemokine N-terminal features attest to a CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell different ligand binding mode and a bias towards activation of ACKR3/CXCR7 migration, J Biol Chem. 286 (37) (2011) 32188–32197. compared with CXCR4 and CXCR3, Br J Pharmacol. 175 (9) (2018) 1419–1438. [66] S. Rajagopal, J. Kim, S. Ahn, S. Craig, C.M. Lam, N.P. Gerard, et al., Beta-arrestin- [92] T. Ngo, B.S. Stephens, M. Gustavsson, L.G. Holden, R. Abagyan, T.M. Handel, et but not G protein-mediated signaling by the “decoy” receptor CXCR7, Proc Natl al., Crosslinking-guided geometry of a complete CXC receptor-chemokine Acad Sci U S A. 107 (2) (2010) 628–632. complex and the basis of chemokine subfamily selectivity, PLoS Biol. 18 (4) [67] Y. Wang, G. Li, A. Stanco, J.E. Long, D. Crawford, G.B. Potter, et al., CXCR4 and (2020), e3000656. CXCR7 have distinct functions in regulating interneuron migration, Neuron. 69 [93] D.J. Wasilko, Z.L. Johnson, M. Ammirati, Y. Che, M.C. Griffor, S. Han, et al., (1) (2011) 61–76. Structural basis for chemokine receptor CCR6 activation by the endogenous [68] Y. Ikeda, H. Kumagai, A. Skach, M. Sato, M. Yanagisawa, Modulation of Circadian protein ligand CCL20, Nat Commun. 11 (1) (2020) 3031. Glucocorticoid Oscillation via Adrenal Opioid-CXCR7 Signaling Alters Emotional [94] S.J. Riutta, O. Larsen, A.E. Getschman, M.M. Rosenkilde, S.T. Hwang, B. Behavior, Cell. 155 (6) (2013) 1323–1336. F. Volkman, Mutational analysis of CCL20 reveals flexibilityof N-terminal amino [69] M. Meyrath, M. Szpakowska, J. Zeiner, L. Massotte, M.P. Merz, T. Benkel, et al., acid composition and length, J Leukoc Biol. 104 (2) (2018) 423–434. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger [95] K.N. Nobles, K. Xiao, S. Ahn, A.K. Shukla, C.M. Lam, S. Rajagopal, et al., Distinct for opioid peptides, Nature communications. 11 (1) (2020) 3033. phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that [70] N. Montpas, G. St-Onge, N. Nama, D. Rhainds, B. Benredjem, M. Girard, et al., encodes differential functions of β-arrestin, Sci Signal. 4 (185) (2011) ra51. Ligand-specific conformational transitions and intracellular transport are [96] C. Doll, J. Konietzko, F. Poll,¨ T. Koch, V. Hollt,¨ S. Schulz, Agonist-selective required for atypical chemokine receptor 3-mediated chemokine scavenging, patterns of μ-opioid receptor phosphorylation revealed by phosphosite-specific J Biol Chem. 293 (3) (2018) 893–905. antibodies, Br J Pharmacol. 164 (2) (2011) 298–307. [71] F. Saaber, D. Schutz, E. Miess, P. Abe, S. Desikan, P. Ashok Kumar, et al., ACKR3 [97] A.J. Butcher, R. Prihandoko, K.C. Kong, P. McWilliams, J.M. Edwards, A. Bottrill, Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not et al., Differential G-protein-coupled receptor phosphorylation provides evidence beta-Arrestin, Cell Rep. 26 (6) (2019) 1473–1488, e9. for a signaling bar code, J Biol Chem. 286 (13) (2011) 11506–11518. [72] H. Wise, The roles played by highly truncated splice variants of G protein-coupled [98] J. Kim, S. Ahn, X.R. Ren, E.J. Whalen, E. Reiter, H. Wei, et al., Functional receptors, J Mol Signal. 7 (1) (2012) 13. antagonism of different G protein-coupled receptor kinases for beta-arrestin- [73] Y.A. Berchiche, T.P. Sakmar, CXC Chemokine Receptor 3 Alternative Splice mediated angiotensin II receptor signaling, Proc Natl Acad Sci U S A. 102 (5) Variants Selectively Activate Different Signaling Pathways, Mol Pharmacol. 90 (2005) 1442–1447. (4) (2016) 483–495. [99] K.E. Komolov, J.L. Benovic, G protein-coupled receptor kinases: Past, present and [74] S.P. Singh, J.F. Foley, H.H. Zhang, D.E. Hurt, J.L. Richards, C.S. Smith, et al., future, Cell Signal. 41 (2018) 17–24. Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 [100] J.A. Pitcher, N.J. Freedman, R.J. Lefkowitz, G protein-coupled receptor kinases, and Is Cell-Type Specific, Mol Pharmacol. 88 (5) (2015) 894–910. Annu Rev Biochem. 67 (1998) 653–692. [75] Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T, Snyder JC, et al. Distinct cortical [101] R.P. Loudon, J.L. Benovic, Expression, purification,and characterization of the G and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal protein-coupled receptor kinase GRK6, J Biol Chem. 269 (36) (1994) unique antipsychotic-like properties. Proc Natl Acad Sci U S A. 2016;113(50): 22691–22697. E8178-E86. [102] P. Kunapuli, J.J. Onorato, M.M. Hosey, J.L. Benovic, Expression, purification,and [76] A. Vroon, C.J. Heijnen, A. Kavelaars, GRKs and arrestins: regulators of migration characterization of the G protein-coupled receptor kinase GRK5, J Biol Chem. 269 and inflammation, J Leukoc Biol. 80 (6) (2006) 1214–1221. (2) (1994) 1099–1105. [77] A. Vroon, C.J. Heijnen, M.S. Lombardi, P.M. Cobelens, F. Mayor, M.G. Caron, et [103] J.M. Busillo, S. Armando, R. Sengupta, O. Meucci, M. Bouvier, J.L. Benovic, Site- al., Reduced GRK2 level in T cells potentiates chemotaxis and signaling in specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases response to CCL4, J Leukoc Biol. 75 (5) (2004) 901–909. and results in differential modulation of CXCR4 signaling, J Biol Chem. 285 (10) [78] T.I. Arnon, Y. Xu, C. Lo, T. Pham, J. An, S. Coughlin, et al., GRK2-dependent (2010) 7805–7817. S1PR1 desensitization is required for lymphocytes to overcome their attraction to [104] W. Mueller, D. Schütz, F. Nagel, S. Schulz, R. Stumm, Hierarchical organization of blood, Science. 333 (6051) (2011) 1898–1903. multi-site phosphorylation at the CXCR4 C terminus, PLoS One. 8 (5) (2013), [79] J.C.W. Mak, T. Hisada, M. Salmon, P.J. Barnes, K.F. Chung, Glucocorticoids e64975. reverse IL-1beta-induced impairment of beta-adrenoceptor-mediated relaxation [105] S.K. Raghuwanshi, Y. Su, V. Singh, K. Haynes, A. Richmond, R.M. Richardson, and up-regulation of G-protein-coupled receptor kinases, British journal of The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled pharmacology. 135 (4) (2002) 987–996. receptor kinases to mediate and regulate leukocyte functions, J Immunol. 189 (6) [80] M.S. Lombardi, A. Kavelaars, P.M. Cobelens, R.E. Schmidt, M. Schedlowski, C. (2012) 2824–2832. J. Heijnen, Adjuvant arthritis induces down-regulation of G protein-coupled [106] J. Luo, J.M. Busillo, R. Stumm, J.L. Benovic, G Protein-Coupled Receptor Kinase 3 receptor kinases in the immune system, J Immunol. 166 (3) (2001) 1635–1640. and Protein Kinase C Phosphorylate the Distal C-Terminal Tail of the Chemokine [81] M.S. Lombardi, A. Kavelaars, M. Schedlowski, J.W. Bijlsma, K.L. Okihara, M. Van Receptor CXCR4 and Mediate Recruitment of, Mol Pharmacol. 91 (6) (2017) de Pol, et al., Decreased expression and activity of G-protein-coupled receptor 554–566. kinases in peripheral blood mononuclear cells of patients with rheumatoid [107] Y. Zheng, L. Qin, N.V. Zacarias, H. de Vries, G.W. Han, M. Gustavsson, et al., arthritis, FASEB J. 13 (6) (1999) 715–725. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists, [82] E. Tutunea-Fatan, F.A. Caetano, R. Gros, S.S. Ferguson, GRK2 targeted knock- Nature. 540 (7633) (2016) 458–461. down results in spontaneous hypertension, and altered vascular GPCR signaling, [108] C. Oswald, M. Rappas, J. Kean, A.S. Dore, J.C. Errey, K. Bennett, et al., J Biol Chem. 290 (8) (2015) 5141–5155. Intracellular allosteric antagonism of the CCR9 receptor, Nature. 540 (7633) [83] J.R. Keys, R.H. Zhou, D.M. Harris, C.A. Druckman, A.D. Eckhart, Vascular smooth (2016) 462–465. muscle overexpression of G protein-coupled receptor kinase 5 elevates blood [109] N.V. Ortiz Zacarias, E.B. Lenselink, AP IJ, Handel TM, Heitman LH., Intracellular pressure, which segregates with sex and is dependent on Gi-mediated signaling, Receptor Modulation: Novel Approach to Target GPCRs, Trends Pharmacol Sci. 39 Circulation. 112 (8) (2005) 1145–1153. (6) (2018) 547–559. [84] A. Vroon, M.S. Lombardi, A. Kavelaars, C.J. Heijnen, Changes in the G-protein- [110] L.M. Wingler, M. Elgeti, D. Hilger, N.R. Latorraca, M.T. Lerch, D.P. Staus, et al., coupled receptor desensitization machinery during relapsing-progressive Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor experimental allergic encephalomyelitis, J Neuroimmunol. 137 (1–2) (2003) Conformations, Cell. 176 (3) (2019), 468-78.e11. 79–86. [111] R.A. Colvin, G.S. Campanella, J. Sun, A.D. Luster, Intracellular domains of CXCR3 [85] I. Kufareva, M. Gustavsson, Y. Zheng, B.S. Stephens, T.M. Handel, What Do that mediate CXCL9, CXCL10, and CXCL11 function, J Biol Chem. 279 (29) Structures Tell Us About Chemokine Receptor Function and Antagonism? Annu (2004) 30219–30227. Rev Biophys. 46 (2017) 175–198. [112] C. Otero, P.S. Eisele, K. Schaeuble, M. Groettrup, D.F. Legler, Distinct motifs in the [86] M. Gustavsson, L. Wang, N. van Gils, B.S. Stephens, P. Zhang, T.J. Schall, et al., chemokine receptor CCR7 regulate signal transduction, receptor trafficking and Structural basis of ligand interaction with atypical chemokine receptor 3, Nat chemotaxis, J Cell Sci. 121 (Pt 16) (2008) 2759–2767. Commun. 8 (2017) 14135. [113] T.J. Cahill, A.R. Thomsen, J.T. Tarrasch, B. Plouffe, A.H. Nguyen, F. Yang, et al., [87] J.S. Burg, J.R. Ingram, A.J. Venkatakrishnan, K.M. Jude, A. Dukkipati, E. Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, N. Feinberg, et al., Structural biology. Structural basis for chemokine recognition signaling, and endocytosis, Proc Natl Acad Sci U S A. 114 (10) (2017) 2562–2567. and activation of a viral G protein-coupled receptor, Science. 347 (6226) (2015) [114] A. Srivastava, B. Gupta, C. Gupta, A.K. Shukla, Emerging Functional Divergence 1113–1117. of β-Arrestin Isoforms in GPCR Function, Trends Endocrinol Metab. 26 (11) [88] M.A. Cox, C.H. Jenh, W. Gonsiorek, J. Fine, S.K. Narula, P.J. Zavodny, et al., (2015) 628–642. Human interferon-inducible 10-kDa protein and human interferon-inducible T
18 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
[115] E. Ghosh, H. Dwivedi, M. Baidya, A. Srivastava, P. Kumari, T. Stepniewski, et al., [143] G. Swaminath, Y. Xiang, T.W. Lee, J. Steenhuis, C. Parnot, B.K. Kobilka, Conformational Sensors and Domain Swapping Reveal Structural and Functional Sequential binding of agonists to the beta2 adrenoceptor. Kinetic evidence for Differences between β-Arrestin Isoforms, Cell Rep. 28 (13) (2019), 3287-99.e6. intermediate conformational states, J Biol Chem. 279 (1) (2004) 686–691. [116] J.S. Smith, L.T. Nicholson, J. Suwanpradid, R.A. Glenn, N.M. Knape, P. Alagesan, [144] Y. Xiang, B.K. Kobilka, Myocyte adrenoceptor signaling pathways, Science. 300 et al., Biased agonists of the chemokine receptor CXCR3 differentially control (5625) (2003) 1530–1532. chemotaxis and inflammation, Sci Signal 11 (2018) 555. [145] L. Neumann, T. Wohland, R.J. Whelan, R.N. Zare, B.K. Kobilka, Functional [117] D.J. Scholten, M. Canals, M. Wijtmans, S. de Munnik, P. Nguyen, D. Verzijl, et al., immobilization of a ligand-activated G-protein-coupled receptor, Chembiochem. Pharmacological characterization of a small-molecule agonist for the chemokine 3 (10) (2002) 993–998. receptor CXCR3, Br J Pharmacol. 166 (3) (2012) 898–911. [146] Efficacy and Safety Study of Mavorixafor in Participants With Warts, [118] M.J. Smit, P. Verdijk, E.M. van der Raaij-Helmer, M. Navis, P.J. Hensbergen, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome. R. Leurs, et al., CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- https://ClinicalTrials.gov/show/NCT03995108. and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 [147] G. Alkhatib, C. Combadiere, C.C. Broder, Y. Feng, P.E. Kennedy, P.M. Murphy, et MAPK nor Akt/PI-3 kinase, Blood. 102 (6) (2003) 1959–1965. al., CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for [119] N. Karin, G. Wildbaum, M. Thelen, Biased signaling pathways via CXCR3 control macrophage-tropic HIV-1, Science. 272 (5270) (1996) 1955–1958. the development and function of CD4+ T cell subsets, Journal of Leukocyte [148] H. Choe, M. Farzan, Y. Sun, N. Sullivan, B. Rollins, P.D. Ponath, et al., The beta- Biology. 99 (6) (2016) 857–862. chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 [120] Y. Zohar, G. Wildbaum, R. Novak, A.L. Salzman, M. Thelen, R. Alon, et al., isolates, Cell. 85 (7) (1996) 1135–1148. CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses [149] H. Deng, R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, et al., autoimmune encephalomyelitis, J Clin Invest. 124 (5) (2014) 2009–2022. Identification of a major co-receptor for primary isolates of HIV-1, Nature. 381 [121] M. Muller, S.L. Carter, M.J. Hofer, P. Manders, D.R. Getts, M.T. Getts, et al., (6584) (1996) 661–666. CXCR3 signaling reduces the severity of experimental autoimmune [150] T. Dragic, V. Litwin, G.P. Allaway, S.R. Martin, Y. Huang, K.A. Nagashima, et al., encephalomyelitis by controlling the parenchymal distribution of effector and HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5, regulatory T cells in the central nervous system, J Immunol. 179 (5) (2007) Nature. 381 (6584) (1996) 667–673. 2774–2786. [151] B.J. Doranz, J. Rucker, Y. Yi, R.J. Smyth, M. Samson, S.C. Peiper, et al., A dual- [122] M.K. Wendt, P.A. Johanesen, N. Kang-Decker, D.G. Binion, V. Shah, M.B. Dwinell, tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes CKR-5, CKR-3, and CKR-2b as fusion cofactors, Cell. 85 (7) (1996) 1149–1158. colonic carcinoma metastasis, Oncogene. 25 (36) (2006) 4986–4997. [152] R. Liu, W.A. Paxton, S. Choe, D. Ceradini, S.R. Martin, R. Horuk, et al., [123] M.K. Wendt, A.N. Cooper, M.B. Dwinell, Epigenetic silencing of CXCL12 increases Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply- the metastatic potential of mammary carcinoma cells, Oncogene. 27 (10) (2008) exposed individuals to HIV-1 infection, Cell. 86 (3) (1996) 367–377. 1461–1471. [153] M. Samson, F. Libert, B.J. Doranz, J. Rucker, C. Liesnard, C.M. Farber, et al., [124] M.K. Wendt, L.J. Drury, R.A. Vongsa, M.B. Dwinell, Constitutive CXCL12 Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of expression induces anoikis in colorectal carcinoma cells, Gastroenterology. 135 the CCR-5 chemokine receptor gene, Nature. 382 (6593) (1996) 722–725. (2) (2008) 508–517. [154] M. Dean, M. Carrington, C. Winkler, G.A. Huttley, M.W. Smith, R. Allikmets, et [125] B. Lagane, K.Y. Chow, K. Balabanian, A. Levoye, J. Harriague, T. Planchenault, et al., Genetic restriction of HIV-1 infection and progression to AIDS by a deletion al., CXCR4 dimerization and beta-arrestin-mediated signaling account for the allele of the CKR5 structural gene. Hemophilia Growth and Development Study, enhanced chemotaxis to CXCL12 in WHIM syndrome, Blood. 112 (1) (2008) Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San 34–44. Francisco City Cohort, ALIVE Study, Science. 273 (5283) (1996) 1856–1862. [126] H. Issafras, S. Angers, S. Bulenger, C. Blanpain, M. Parmentier, C. Labbe-Jullie, et [155] Y. Huang, W.A. Paxton, S.M. Wolinsky, A.U. Neumann, L. Zhang, T. He, et al., The al., Constitutive agonist-independent CCR5 oligomerization and antibody- role of a mutant CCR5 allele in HIV-1 transmission and disease progression, Nat mediated clustering occurring at physiological levels of receptors, J Biol Chem. Med. 2 (11) (1996) 1240–1243. 277 (38) (2002) 34666–34673. [156] W.A. Paxton, S.R. Martin, D. Tse, T.R. O’Brien, J. Skurnick, N.L. VanDevanter, et [127] Y. Percherancier, Y.A. Berchiche, I. Slight, R. Volkmer-Engert, H. Tamamura, al., Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who N. Fujii, et al., Bioluminescence resonance energy transfer reveals ligand-induced remain uninfected despite multiple high-risk sexual exposure, Nat Med. 2 (4) conformational changes in CXCR4 homo- and heterodimers, J Biol Chem. 280 (1996) 412–417. (11) (2005) 9895–9903. [157] N. Veljkovic, J. Vucicevic, S. Tassini, S. Glisic, V. Veljkovic, M. Radi, Preclinical [128] F. Trettel, S. Di Bartolomeo, C. Lauro, M. Catalano, M.T. Ciotti, C. Limatola, discovery and development of maraviroc for the treatment of HIV, Expert Opin Ligand-independent CXCR2 dimerization, J Biol Chem. 278 (42) (2003) Drug Discov. 10 (6) (2015) 671–684. 40980–40988. [158] A. De Luca, P. Pezzotti, C. Boucher, M. Doring, F. Incardona, R. Kaiser, et al., [129] R. Forster, A. Schubel, D. Breitfeld, E. Kremmer, I. Renner-Muller, E. Wolf, et al., Clinical use, efficacy, and durability of maraviroc for antiretroviral therapy in CCR7 coordinates the primary immune response by establishing functional routine care: A European survey, PLoS One. 14 (11) (2019), e0225381. microenvironments in secondary lymphoid organs, Cell. 99 (1) (1999) 23–33. [159] C.M. Hogan, S.M. Hammer, Host determinants in HIV infection and disease. Part [130] G. Bardi, M. Lipp, M. Baggiolini, P. Loetscher, The T cell chemokine receptor 2: genetic factors and implications for antiretroviral therapeutics, Ann Intern CCR7 is internalized on stimulation with ELC, but not with SLC, Eur J Immunol. Med. 134 (10) (2001) 978–996. 31 (11) (2001) 3291–3297. [160] M. Mack, B. Luckow, P.J. Nelson, J. Cihak, G. Simmons, P.R. Clapham, et al., [131] M.R. Britschgi, S. Favre, S.A. Luther, CCL21 is sufficientto mediate DC migration, Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a maturation and function in the absence of CCL19, Eur J Immunol. 40 (5) (2010) novel inhibitory mechanism of HIV infectivity, J Exp Med. 187 (8) (1998) 1266–1271. 1215–1224. [132] A.J. Zweemer, J. Toraskar, L.H. Heitman, AP IJ., Bias in chemokine receptor [161] A.J. Marozsan, V.S. Torre, M. Johnson, S.C. Ball, J.V. Cross, D.J. Templeton, et al., signalling, Trends Immunol. 35 (6) (2014) 243–252. Mechanisms involved in stimulation of human immunodeficiency virus type 1 [133] S.S. Lieberman-Blum, H.B. Fung, J.C. Bandres, Maraviroc: a CCR5-receptor replication by aminooxypentane RANTES, J Virol. 75 (18) (2001) 8624–8638. antagonist for the treatment of HIV-1 infection, Clin Ther. 30 (7) (2008) [162] H. Gaertner, F. Cerini, J.M. Escola, G. Kuenzi, A. Melotti, R. Offord, et al., Highly 1228–1250. potent, fully recombinant anti-HIV chemokines: reengineering a low-cost [134] G. Fatkenheuer, A.L. Pozniak, M.A. Johnson, A. Plettenberg, S. Staszewski, A. microbicide, Proc Natl Acad Sci U S A. 105 (46) (2008) 17706–17711. I. Hoepelman, et al., Efficacy of short-term monotherapy with maraviroc, a new [163] S.R. Galvin, M.S. Cohen, The role of sexually transmitted diseases in HIV CCR5 antagonist, in patients infected with HIV-1, Nat Med. 11 (11) (2005) transmission, Nat Rev Microbiol. 2 (1) (2004) 33–42. 1170–1172. [164] C. Bonsch, M. Munteanu, I. Rossitto-Borlat, A. Furstenberg, O. Hartley, Potent [135] E. De Clercq, The AMD3100 story: the path to the discovery of a stem cell Anti-HIV Chemokine Analogs Direct Post-Endocytic Sorting of CCR5, PLoS One. mobilizer (Mozobil), Biochem Pharmacol. 77 (11) (2009) 1655–1664. 10 (4) (2015), e0125396. [136] E. De Clercq, N. Yamamoto, R. Pauwels, J. Balzarini, M. Witvrouw, K. De Vreese, [165] M. Metzemaekers, V. Vanheule, R. Janssens, S. Struyf, P. Proost, Overview of the et al., Highly potent and selective inhibition of human immunodeficiencyvirus by Mechanisms that May Contribute to the Non-Redundant Activities of Interferon- the bicyclam derivative JM3100, Antimicrob Agents Chemother. 38 (4) (1994) Inducible CXC Chemokine Receptor 3 Ligands, Front Immunol. 8 (2017) 1970. 668–674. [166] J.R. Groom, A.D. Luster, CXCR3 in T cell function, Exp Cell Res. 317 (5) (2011) [137] G.A. Donzella, D. Schols, S.W. Lin, J.A. Este, K.A. Nagashima, P.J. Maddon, et al., 620–631. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor, [167] P.T. Kuo, Z. Zeng, N. Salim, S. Mattarollo, J.W. Wells, G.R. Leggatt, The Role of Nat Med. 4 (1) (1998) 72–77. CXCR3 and Its Chemokine Ligands in Skin Disease and Cancer, Front Med [138] E. De Clercq, Mozobil(R) (Plerixafor, AMD3100), 10 years after its approval by (Lausanne). 5 (2018) 271. the US Food and Drug Administration, Antivir Chem Chemother. 27 (2019), [168] B. Hitchinson, J.M. Eby, X. Gao, F. Guite-Vinet, J.J. Ziarek, H. Abdelkarim, et al., 2040206619829382. Biased antagonism of CXCR4 avoids antagonist tolerance, Sci Signal. 11 (552) [139] S.P. Fricker, Physiology and pharmacology of plerixafor, Transfus Med Hemother. (2018). 40 (4) (2013) 237–245. [169] J. Corbisier, A. Huszagh, C. Gales,´ M. Parmentier, J.-Y. Springael, Partial agonist [140] T.A. Ollila, I. Sahin, A.J. Olszewski, Mogamulizumab: a new tool for management and biased signaling properties of the synthetic enantiomers J113863/UCB35625 of cutaneous T-cell lymphoma, Onco Targets Ther. 12 (2019) 1085–1094. at chemokine receptors CCR2 and CCR5, 2016 jbc.M116.757559. [141] A. Mullard, FDA approves second GPCR-targeted antibody, Nat Rev Drug Discov. [170] R. Feniger-Barish, M. Ran, A. Zaslaver, A. Ben-Baruch, Differential modes of 17 (9) (2018) 613. regulation of cxc chemokine-induced internalization and recycling of human [142] M. Miao, E. De Clercq, G. Li, Clinical significance of chemokine receptor CXCR1 and CXCR2, Cytokine. 11 (12) (1999) 996–1009. antagonists, Expert Opin Drug Metab Toxicol. 16 (1) (2020) 11–30.
19 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
[171] M. Allegretti, R. Bertini, M.C. Cesta, C. Bizzarri, R. Di Bitondo, V. Di Cioccio, et [195] J. Hesselgesser, H.P. Ng, M. Liang, W. Zheng, K. May, J.G. Bauman, et al., al., 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel Identificationand characterization of small molecule functional antagonists of the noncompetitive CXCL8 inhibitors, J Med Chem. 48 (13) (2005) 4312–4331. CCR1 chemokine receptor, J Biol Chem. 273 (25) (1998) 15687–15692. [172] R. Bertini, M. Allegretti, C. Bizzarri, A. Moriconi, M. Locati, G. Zampella, et al., [196] O. Zirafi,K.A. Kim, L. Standker, K.B. Mohr, D. Sauter, A. Heigele, et al., Discovery Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors and characterization of an endogenous CXCR4 antagonist, Cell Rep. 11 (5) (2015) CXCR1 and CXCR2: prevention of reperfusion injury, Proc Natl Acad Sci U S A. 737–747. 101 (32) (2004) 11791–11796. [197] J.A. Burger, D.J. Stewart, CXCR4 chemokine receptor antagonists: perspectives in [173] H.Y. Kim, J.H. Choi, Y.J. Kang, S.Y. Park, H.C. Choi, H.S. Kim, Reparixin, an SCLC, Expert Opin Investig Drugs. 18 (4) (2009) 481–490. inhibitor of CXCR1 and CXCR2 receptor activation, attenuates blood pressure and [198] Safety and PK/PD of TG-0054 in Multiple Myeloma, Non-Hodgkin Lymphoma and hypertension-related mediators expression in spontaneously hypertensive rats, Hodgkin Disease Patients. https://ClinicalTrials.gov/show/NCT01018979;, 2015. Biol Pharm Bull. 34 (1) (2011) 120–127. [199] N.B. Shelke, R. Kadam, P. Tyagi, V.R. Rao, U.B. Kompella, Intravitreal Poly(L- [174] R. Bertini, L.S. Barcelos, A.R. Beccari, B. Cavalieri, A. Moriconi, C. Bizzarri, et al., lactide) Microparticles Sustain Retinal and Choroidal Delivery of TG-0054, a Receptor binding mode and pharmacological characterization of a potent and Hydrophilic Drug Intended for Neovascular Diseases, Drug Deliv Transl Res. 1 (1) selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor, Br J (2011) 76–90. Pharmacol. 165 (2) (2012) 436–454. [200] W.T. Hsu, H.Y. Jui, Y.H. Huang, M.Y. Su, Y.W. Wu, W.Y. Tseng, et al., CXCR4 [175] D.Y. Maeda, A.M. Peck, A.D. Schuler, M.T. Quinn, L.N. Kirpotina, W.N. Wicomb, Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates et al., Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl] Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 Myocardial Infarction, Cell Transplant. 24 (7) (2015) 1313–1328. and CXCR2, J Med Chem. 57 (20) (2014) 8378–8397. [201] Safety and Activity of the Oral HIV Entry Inhibitor AMD11070 in HIV Infected [176] S.P. Matzer, J. Zombou, H.M. Sarau, M. Rollinghoff, H.U. Beuscher, A synthetic, Patients. https://ClinicalTrials.gov/show/NCT00089466;, 2012. non-peptide CXCR2 antagonist blocks MIP-2-induced neutrophil migration in [202] G.J. Bridger, R.T. Skerlj, P.E. Hernandez-Abad, D.E. Bogucki, Z. Wang, Y. Zhou, et mice, Immunobiology. 209 (3) (2004) 225–233. al., Synthesis and structure-activity relationships of azamacrocyclic C-X-C [177] S.I. Rennard, D.C. Dale, J.F. Donohue, F. Kanniess, H. Magnussen, E. chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic R. Sutherland, et al., CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication, J Med Chem. 53 Trial for Chronic Obstructive Pulmonary Disease, Am J Respir Crit Care Med. 191 (3) (2010) 1250–1260. (9) (2015) 1001–1011. [203] R.T. Skerlj, G.J. Bridger, A. Kaller, E.J. McEachern, J.B. Crawford, Y. Zhou, et al., [178] Efficacy and Safety Study of Navarixin (MK-7123) in Combination With Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 Pembrolizumab (MK-3475) in Adults With Selected Advanced/Metastatic Solid antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication, J Med Tumors (MK-7123-034). https://ClinicalTrials.gov/show/NCT03473925;, 2018. Chem. 53 (8) (2010) 3376–3388. [179] M.P. Dwyer, Y. Yu, J. Chao, C. Aki, J. Chao, P. Biju, et al., Discovery of 2-hydroxy- [204] A Dose Determination and Safety Study of X4P-001 (Mavorixafor) in Participants N,N-dimethyl-3-{2-[[(R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4- With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) dioxocyclobut-1-enylamino}benzamide (SCH 527123): a potent, orally Syndrome. https://ClinicalTrials.gov/show/NCT03005327;, 2019. bioavailable CXCR2/CXCR1 receptor antagonist, J Med Chem. 49 (26) (2006) [205] X4P-001 and Pembrolizumab in Patients With Advanced Melanoma. https 7603–7606. ://ClinicalTrials.gov/show/NCT02823405;, 2019. [180] J. Busch-Petersen, D.C. Carpenter, M. Burman, J. Foley, G.E. Hunsberger, D. [206] MSX-122 Administered Orally in Patients With Refractory Metastatic or Locally J. Kilian, et al., Danirixin: A Reversible and Selective Antagonist of the CXC Advanced Solid Tumors. https://ClinicalTrials.gov/show/NCT00591682;, 2008. Chemokine Receptor 2, J Pharmacol Exp Ther. 362 (2) (2017) 338–346. [207] Z. Liang, W. Zhan, A. Zhu, Y. Yoon, S. Lin, M. Sasaki, et al., Development of a [181] A.L. Lazaar, B.E. Miller, M. Tabberer, J. Yonchuk, N. Leidy, C. Ambery, et al., unique small molecule modulator of CXCR4, PLoS One. 7 (4) (2012), e34038. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD, [208] D. Wong, W. Korz, Translating an Antagonist of Chemokine Receptor CXCR4: Eur Respir J. 52 (4) (2018). from bench to bedside, Clin Cancer Res. 14 (24) (2008) 7975–7980. [182] B.E. Miller, S. Mistry, K. Smart, P. Connolly, D.C. Carpenter, H. Cooray, et al., The [209] Safety and Efficacy of POL6326 for Mobilization/Transplant of Sibling Donor in pharmacokinetics and pharmacodynamics of danirixin (GSK1325756)–a selective Patients With Hematologic Malignancies: https://ClinicalTrials.gov/show/NCT CXCR2 antagonist –in healthy adult subjects, BMC Pharmacol Toxicol. 16 (2015) 01413568; 2011. 18. [210] A. Sachpatzidis, B.K. Benton, J.P. Manfredi, H. Wang, A. Hamilton, H. [183] A.F. Bento, D.F. Leite, R.F. Claudino, D.B. Hara, P.C. Leal, J.B. Calixto, The G. Dohlman, et al., Identification of allosteric peptide agonists of CXCR4, J Biol selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute Chem. 278 (2) (2003) 896–907. experimental colitis in mice, J Leukoc Biol. 84 (4) (2008) 1213–1221. [211] J. Quoyer, J.M. Janz, J. Luo, Y. Ren, S. Armando, V. Lukashova, et al., Pepducin [184] J.R. White, J.M. Lee, P.R. Young, R.P. Hertzberg, A.J. Jurewicz, M.A. Chaikin, et targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring al., Identification of a potent, selective non-peptide CXCR2 antagonist that activation of the inhibitory G protein, Proc Natl Acad Sci U S A. 110 (52) (2013) inhibits interleukin-8-induced neutrophil migration, J Biol Chem. 273 (17) (1998) E5088–E5097. 10095–10098. [212] B. Tchernychev, Y. Ren, P. Sachdev, J.M. Janz, L. Haggis, A. O’Shea, et al., [185] D.J. Nicholls, K. Wiley, I. Dainty, F. MacIntosh, C. Phillips, A. Gaw, et al., Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow Pharmacological characterization of AZD5069, a slowly reversible CXC hematopoietic cells, Proc Natl Acad Sci U S A. 107 (51) (2010) 22255–22259. chemokine receptor 2 antagonist, J Pharmacol Exp Ther. 353 (2) (2015) 340–350. [213] P. Dimond, K. Carlson, M. Bouvier, C. Gerard, L. Xu, L. Covic, et al., G protein- [186] A. Sauty, R.A. Colvin, L. Wagner, S. Rochat, F. Spertini, A.D. Luster, CXCR3 coupled receptor modulation with pepducins: moving closer to the clinic, Ann N Y internalization following T cell-endothelial cell contact: preferential role of IFN- Acad Sci. 1226 (2011) 34–49. inducible T cell alpha chemoattractant (CXCL11), J Immunol. 167 (12) (2001) [214] Y. Xu, S. Duggineni, S. Espitia, D.D. Richman, J. An, Z. Huang, A synthetic 7084–7093. bivalent ligand of CXCR4 inhibits HIV infection, Biochem Biophys Res Commun. [187] M. Müller, S.L. Carter, M.J. Hofer, P. Manders, D.R. Getts, M.T. Getts, et al., 435 (4) (2013) 646–650. CXCR3 Signaling Reduces the Severity of Experimental Autoimmune [215] T. Murakami, T. Nakajima, Y. Koyanagi, K. Tachibana, N. Fujii, H. Tamamura, et Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and al., A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 Regulatory T Cells in the Central Nervous System, The Journal of Immunology. infection, J Exp Med. 186 (8) (1997) 1389–1393. 179 (5) (2007) 2774–2786. [216] D. Karpova, S. Brauninger, E. Wiercinska, A. Kramer, B. Stock, J. Graff, et al., [188] D. Scholten, M. Canals, M. Wijtmans, S. De Munnik, P. Nguyen, D. Verzijl, et al., Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist Pharmacological characterization of a small-molecule agonist for the chemokine POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial, receptor CXCR3. 166 (3) (2012) 898–911. J Transl Med. 15 (1) (2017) 2. [189] J.S. Smith, L.T. Nicholson, J. Suwanpradid, R.A. Glenn, N.M. Knape, P. Alagesan, [217] S. Pernas, M. Martin, P.A. Kaufman, M. Gil-Martin, P. Gomez Pardo, S. Lopez- et al., Biased agonists of the chemokine receptor CXCR3 differentially control Tarruella, et al., Balixafortide plus eribulin in HER2-negative metastatic breast chemotaxis and inflammation, Science Signaling 11 (555) (2018) eaaq1075. cancer: a phase 1, single-arm, dose-escalation trial, Lancet Oncol. 19 (6) (2018) [190] L. Milanos, R. Brox, T. Frank, G. Poklukar, R. Palmisano, R. Waibel, et al., 812–824. Discovery and Characterization of Biased Allosteric Agonists of the Chemokine [218] Pivotal Study in HER2 Negative, Locally Recurrent or Metastatic Breast Cancer: Receptor CXCR3, Journal of Medicinal Chemistry. 59 (5) (2016) 2222–2243. https://ClinicalTrials.gov/show/NCT03786094; 2018. [191] R. Brox, L. Milanos, N. Saleh, P. Baumeister, A. Buschauer, D. Hofmann, et al., [219] H. Tamamura, Y. Xu, T. Hattori, X. Zhang, R. Arakaki, K. Kanbara, et al., A low- Molecular Mechanisms of Biased and Probe-Dependent Signaling at CXC-Motif molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti- Chemokine Receptor CXCR3 Induced by Negative Allosteric Modulators, Mol HIV peptide T140, Biochem Biophys Res Commun. 253 (3) (1998) 877–882. Pharmacol. 93 (4) (2018) 309–322. [220] M. Lefrancois, M.R. Lefebvre, G. Saint-Onge, P.E. Boulais, S. Lamothe, R. Leduc, et [192] K. Boye, C. Billottet, N. Pujol, I.D. Alves, A. Bikfalvi, Ligand activation induces al., Agonists for the Chemokine Receptor CXCR4, ACS Med Chem Lett. 2 (8) different conformational changes in CXCR3 receptor isoforms as evidenced by (2011) 597–602. plasmon waveguide resonance (PWR), Sci Rep. 7 (1) (2017) 10703. [221] C.E. Mona, E. Besserer-Offroy, J. Cabana, R. Leduc, P. Lavigne, N. Heveker, et al., [193] C.H. Jenh, M.A. Cox, L. Cui, E.P. Reich, L. Sullivan, S.C. Chen, et al., A selective Design, synthesis, and biological evaluation of CXCR4 ligands, Org Biomol Chem. and potent CXCR3 antagonist SCH 546738 attenuates the development of 14 (43) (2016) 10298–10311. autoimmune diseases and delays graft rejection, BMC Immunol. 13 (2012) 2. [222] N.C. Kaneider, A. Agarwal, A.J. Leger, A. Kuliopulos, Reversing systemic [194] V. Bernat, R. Brox, M.R. Heinrich, Y.P. Auberson, N. Tschammer, Ligand-biased inflammatory response syndrome with chemokine receptor pepducins, Nat Med. and probe-dependent modulation of chemokine receptor CXCR3 signaling by 11 (6) (2005) 661–665. negative allosteric modulators, ChemMedChem. 10 (3) (2015) 566–574.
20 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
[223] K. O’Callaghan, L. Lee, N. Nguyen, M.Y. Hsieh, N.C. Kaneider, A.K. Klein, et al., [248] P.C. Jensen, S. Thiele, A. Steen, A. Elder, R. Kolbeck, S. Ghosh, et al., Reversed Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic binding of a small molecule ligand in homologous chemokine receptors - leukemia, Blood. 119 (7) (2012) 1717–1725. differential role of extracellular loop 2, Br J Pharmacol. 166 (1) (2012) 258–275. [224] A. Zhu, W. Zhan, Z. Liang, Y. Yoon, H. Yang, H.E. Grossniklaus, et al., [249] Y.A. Berchiche, S. Gravel, M.E. Pelletier, G. St-Onge, N. Heveker, Different effects Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with of the different natural CC chemokine receptor 2b ligands on beta-arrestin high specificity, J Med Chem. 53 (24) (2010) 8556–8568. recruitment, Galphai signaling, and receptor internalization, Mol Pharmacol. 79 [225] S. Jenkinson, M. Thomson, D. McCoy, M. Edelstein, S. Danehower, W. Lawrence, (3) (2011) 488–498. et al., Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent [250] J. An, Y. Xue, M. Long, G. Zhang, J. Zhang, H. Su, Targeting CCR2 with its noncompetitive CXCR4 receptor antagonist, Antimicrob Agents Chemother. 54 antagonist suppresses viability, motility and invasion by downregulating MMP-9 (2) (2010) 817–824. expression in non-small cell lung cancer cells, Oncotarget. 8 (24) (2017) [226] V.M. Truax, H. Zhao, B.M. Katzman, A.R. Prosser, A.A. Alcaraz, M.T. Saindane, et 39230–39240. al., Discovery of tetrahydroisoquinoline-based CXCR4 antagonists, ACS Med [251] N. Shin, F. Baribaud, K. Wang, G. Yang, R. Wynn, M.B. Covington, et al., Chem Lett. 4 (11) (2013) 1025–1030. Pharmacological characterization of INCB3344, a small molecule antagonist of [227] G. Thoma, M.B. Streiff, J. Kovarik, F. Glickman, T. Wagner, C. Beerli, et al., Orally human CCR2, Biochem Biophys Res Commun. 387 (2) (2009) 251–255. bioavailable isothioureas block function of the chemokine receptor CXCR4 in [252] A.J. Zweemer, I. Nederpelt, H. Vrieling, S. Hafith, M.L. Doornbos, H. de Vries, et vitro and in vivo, J Med Chem. 51 (24) (2008) 7915–7920. al., Multiple binding sites for small-molecule antagonists at the CC chemokine [228] B. Wu, E.Y. Chien, C.D. Mol, G. Fenalti, W. Liu, V. Katritch, et al., Structures of the receptor 2, Mol Pharmacol. 84 (4) (2013) 551–561. CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists, [253] M. Vilums, A.J. Zweemer, S. Dekkers, Y. Askar, H. de Vries, J. Saunders, et al., Science. 330 (6007) (2010) 1066–1071. Design and synthesis of novel small molecule CCR2 antagonists: evaluation of 4- [229] N. Zhou, J. Fang, E. Acheampong, M. Mukhtar, R.J. Pomerantz, Binding of aminopiperidine derivatives, Bioorg Med Chem Lett. 24 (23) (2014) 5377–5380. ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by [254] I. Bot, N.V. Ortiz Zacarias, W.E. de Witte, H. de Vries, P.J. van Santbrink, D. van HIV-1, Virology. 312 (1) (2003) 196–203. der Velden, et al., A novel CCR2 antagonist inhibits atherogenesis in apoE [230] B.J. Doranz, L.G. Filion, F. Diaz-Mitoma, D.S. Sitar, J. Sahai, F. Baribaud, et al., deficient mice by achieving high receptor occupancy, Sci Rep. 7 (1) (2017) 52. Safe use of the CXCR4 inhibitor ALX40-4C in humans, AIDS Res Hum [255] T. Wisniewski, E. Bayne, J. Flanagan, Q. Shao, R. Wnek, S. Matheravidathu, et al., Retroviruses. 17 (6) (2001) 475–486. Assessment of chemokine receptor function on monocytes in whole blood: In vitro [231] F. Chu, H.S. Li, X. Liu, J. Cao, W. Ma, Y. Ma, et al., CXCR5(+)CD8(+) T cells are a and ex vivo evaluations of a CCR2 antagonist, J Immunol Methods. 352 (1–2) distinct functional subset with an antitumor activity, Leukemia. 33 (11) (2019) (2010) 101–110. 2640–2653. [256] A. Mueller, N.G. Mahmoud, M.C. Goedecke, J.A. McKeating, P.G. Strange, [232] M.G. Kazanietz, M. Durando, M. Cooke, CXCL13 and Its Receptor CXCR5 in Pharmacological characterization of the chemokine receptor, CCR5, Br J Cancer: Inflammation, Immune Response, and Beyond, Front Endocrinol Pharmacol. 135 (4) (2002) 1033–1043. (Lausanne). 10 (2019) 471. [257] J.R. White, J.M. Lee, K. Dede, C.S. Imburgia, A.J. Jurewicz, G. Chan, et al., [233] A.S. Ashhurst, M. Florido, L.C.W. Lin, D. Quan, E. Armitage, S.A. Stifter, et al., Identification of potent, selective non-peptide CC chemokine receptor-3 CXCR6-Deficiency Improves the Control of Pulmonary Mycobacterium antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4- tuberculosis and Influenza Infection Independent of T-Lymphocyte Recruitment induced eosinophil migration, J Biol Chem. 275 (47) (2000) 36626–36631. to the Lungs, Front Immunol. 10 (2019) 339. [258] M. Grozdanovic, K.G. Laffey, H. Abdelkarim, B. Hitchinson, A. Harijith, H. [234] A.N. Wein, S.R. McMaster, S. Takamura, P.R. Dunbar, E.K. Cartwright, S. G. Moon, et al., Novel peptide nanoparticle-biased antagonist of CCR3 blocks L. Hayward, et al., CXCR6 regulates localization of tissue-resident memory CD8 T eosinophil recruitment and airway hyperresponsiveness, J Allergy Clin Immunol. cells to the airways, J Exp Med. 216 (12) (2019) 2748–2762. 143 (2) (2019) 669–680, e12. [235] S. Peddibhotla, P.M. Hershberger, R. Jason Kirby, E. Sugarman, P.R. Maloney, [259] H. Neighbour, L.P. Boulet, C. Lemiere, R. Sehmi, R. Leigh, A.R. Sousa, et al., E. Hampton Sessions, et al., Discovery of small molecule antagonists of chemokine Safety and efficacy of an oral CCR3 antagonist in patients with asthma and receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a eosinophilic bronchitis: a randomized, placebo-controlled clinical trial, Clin Exp model of hepatocellular carcinoma, Bioorg Med Chem Lett. 30 (4) (2020) 126899. Allergy. 44 (4) (2014) 508–516. [236] I. Sabroe, M.J. Peck, B.J. Van Keulen, A. Jorritsma, G. Simmons, P.R. Clapham, et [260] J.M. Viney, D.P. Andrew, R.M. Phillips, A. Meiser, P. Patel, M. Lennartz-Walker, al., A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent et al., Distinct conformations of the chemokine receptor CCR4 with implications inhibition of eosinophil function and CCR3-mediated HIV-1 entry, J Biol Chem. for its targeting in allergy, J Immunol. 192 (7) (2014) 3419–3427. 275 (34) (2000) 25985–25992. [261] K. Bonner, J.E. Pease, C.J. Corrigan, P. Clark, A.B. Kay, CCL17/thymus and [237] F.L. de Mendonca, P.C. da Fonseca, R.M. Phillips, J.W. Saldanha, T.J. Williams, J. activation-regulated chemokine induces calcitonin gene-related peptide in human E. Pease, Site-directed mutagenesis of CC chemokine receptor 1 reveals the airway epithelial cells through CCR4, J Allergy Clin Immunol. 132 (4) (2013), mechanism of action of UCB 35625, a small molecule chemokine receptor 942-50 e1-3. antagonist, J Biol Chem. 280 (6) (2005) 4808–4816. [262] M. Mariani, R. Lang, E. Binda, P. Panina-Bordignon, D. D’Ambrosio, Dominance [238] E.L. Wise, C. Duchesnes, P.C. da Fonseca, R.A. Allen, T.J. Williams, J.E. Pease, of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization Small molecule receptor agonists and antagonists of CCR3 provide insight into and internalization on human Th2 cells, Eur J Immunol. 34 (1) (2004) 231–240. mechanisms of chemokine receptor activation, J Biol Chem. 282 (38) (2007) [263] Y. Zhang, Y. Wu, H. Qi, J. Xiao, H. Gong, Y. Zhang, et al., A new antagonist for 27935–27943. CCR4 attenuates allergic lung inflammationin a mouse model of asthma, Sci Rep. [239] M. Amat, C.F. Benjamim, L.M. Williams, N. Prats, E. Terricabras, J. Beleta, et al., 7 (1) (2017) 15038. Pharmacological blockade of CCR1 ameliorates murine arthritis and alters [264] C. Watson, S. Jenkinson, W. Kazmierski, T. Kenakin, The CCR5 receptor-based cytokine networks in vivo, Br J Pharmacol. 149 (6) (2006) 666–675. mechanism of action of 873140, a potent allosteric noncompetitive HIV entry [240] S. Shahrara, A.E. Proudfoot, J.M. Woods, J.H. Ruth, M.A. Amin, C.C. Park, et al., inhibitor, Mol Pharmacol. 67 (4) (2005) 1268–1282. Amelioration of rat adjuvant-induced arthritis by Met-RANTES, Arthritis Rheum. [265] W.G. Nichols, H.M. Steel, T. Bonny, K. Adkison, L. Curtis, J. Millard, et al., 52 (6) (2005) 1907–1919. Hepatotoxicity observed in clinical trials of aplaviroc (GW873140), Antimicrob [241] C. Plater-Zyberk, A.J. Hoogewerf, A.E. Proudfoot, C.A. Power, T.N. Wells, Effect Agents Chemother. 52 (3) (2008) 858–865. of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 [266] M. Baba, K. Takashima, H. Miyake, N. Kanzaki, K. Teshima, X. Wang, et al., TAK- mice, Immunol Lett. 57 (1–3) (1997) 117–120. 652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in [242] Y. Huang, S. Jiao, X. Tao, Q. Tang, W. Jiao, J. Xiao, et al., Met-CCL5 represents an vitro and has favorable pharmacokinetics in humans, Antimicrob Agents immunotherapy strategy to ameliorate rabies virus infection, Chemother. 49 (11) (2005) 4584–4591. J Neuroinflammation. 11 (2014) 146. [267] J.A. Este, TAK-779 (Takeda), Curr Opin Investig Drugs. 2 (3) (2001) 354–356. [243] D.J. Dairaghi, P. Zhang, Y. Wang, L.C. Seitz, D.A. Johnson, S. Miao, et al., [268] T. Kummerle, C. Lehmann, P. Hartmann, C. Wyen, G. Fatkenheuer, Vicriviroc: a Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCR5 antagonist for treatment-experienced patients with HIV-1 infection, Expert CCX354 in healthy human subjects: implications for selection of clinical dose, Opin Investig Drugs. 18 (11) (2009) 1773–1785. Clin Pharmacol Ther. 89 (5) (2011) 726–734. [269] Y. Saita, E. Kodama, M. Orita, M. Kondo, T. Miyazaki, K. Sudo, et al., Structural [244] R.P. Gladue, L.A. Tylaska, W.H. Brissette, P.D. Lira, J.C. Kath, C.S. Poss, et al., CP- basis for the interaction of CCR5 with a small molecule, functionally selective 481,715, a potent and selective CCR1 antagonist with potential therapeutic CCR5 agonist, J Immunol. 177 (5) (2006) 3116–3122. implications for inflammatory diseases, J Biol Chem. 278 (42) (2003) [270] Y. Saita, M. Kondo, Y. Shimizu, Species selectivity of small-molecular antagonists 40473–40480. for the CCR5 chemokine receptor, Int Immunopharmacol. 7 (12) (2007) [245] R.P. Gladue, M.F. Brown, S.H. Zwillich, CCR1 antagonists: what have we learned 1528–1534. from clinical trials, Curr Top Med Chem. 10 (13) (2010) 1268–1277. [271] A. Palani, S. Shapiro, H. Josien, T. Bara, J.W. Clader, W.J. Greenlee, et al., [246] C.E. Vergunst, D.M. Gerlag, L. von Moltke, M. Karol, T. Wyant, X. Chi, et al., Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV efficacy,pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in activity, J Med Chem. 45 (14) (2002) 3143–3160. a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept [272] A.W. van Kuijk, C.E. Vergunst, D.M. Gerlag, B. Bresnihan, J.J. Gomez-Reino, study, Arthritis Rheum. 60 (12) (2009) 3572–3581. R. Rouzier, et al., CCR5 blockade in rheumatoid arthritis: a randomised, double- [247] P.P. Tak, A. Balanescu, V. Tseluyko, S. Bojin, E. Drescher, D. Dairaghi, et al., blind, placebo-controlled clinical trial, Ann Rheum Dis. 69 (11) (2010) Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid 2013–2016. arthritis: CARAT-2, a randomised, placebo controlled clinical trial, Ann Rheum [273] P. Ghadjar, C. Rubie, D.M. Aebersold, U. Keilholz, The chemokine CCL20 and its Dis. 72 (3) (2013) 337–344. receptor CCR6 in human malignancy with focus on colorectal cancer, Int J Cancer. 125 (4) (2009) 741–745.
21 D.S. Eiger et al. Cellular Signalling 78 (2021) 109862
[274] V.O. Frick, C. Rubie, K. Kolsch, M. Wagner, P. Ghadjar, S. Graeber, et al., CCR6/ chemokine receptor CCR10 that show efficacy in the murine DNFB model of CCL20 chemokine expression profile in distinct colorectal malignancies, Scand J contact hypersensitivity, Bioorg Med Chem Lett. 26 (21) (2016) 5277–5283. Immunol. 78 (3) (2013) 298–305. [294] M. Lee, Y. Lee, J. Song, J. Lee, S.Y. Chang, Tissue-specific Role of CX3CR1 [275] Y. Shimizu, H. Murata, Y. Kashii, K. Hirano, H. Kunitani, K. Higuchi, et al., CC- Expressing Immune Cells and Their Relationships with Human Disease, Immune chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha Netw. 18 (1) (2018), e5. might be involved in the amplificationof local necroinflammatoryresponse in the [295] F. Shen, Y. Zhang, D.L. Jernigan, X. Feng, J. Yan, F.U. Garcia, et al., Novel Small- liver, Hepatology. 34 (2) (2001) 311–319. Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of [276] R. Varona, V. Cadenas, L. Gomez, A.C. Martinez, G. Marquez, CCR6 regulates CD4 Breast Cancer Cells, Mol Cancer Res. 14 (6) (2016) 518–527. + T-cell-mediated acute graft-versus-host disease responses, Blood. 106 (1) [296] M.C. Stout, S. Narayan, E.S. Pillet, J.M. Salvino, P.M. Campbell, Inhibition of (2005) 18–26. CX3CR1 reduces cell motility and viability in pancreatic adenocarcinoma [277] M.Y. Lu, S.S. Lu, S.L. Chang, F. Liao, The Phosphorylation of CCR6 on Distinct epithelial cells, Biochem Biophys Res Commun. 495 (3) (2018) 2264–2269. Ser/Thr Residues in the Carboxyl Terminus Differentially Regulates Biological [297] S. Abdelmoaty, H. Arthur, I. Spyridopoulos, M. Wagberg, R.F. Danielson, Function, Front Immunol. 9 (2018) 415. J. Pernow, et al., 5234KAND567, the first selective small molecule CX3CR1 [278] A.E. Getschman, Y. Imai, O. Larsen, F.C. Peterson, X. Wu, M.M. Rosenkilde, et al., antagonist in clinical development, medates anti-inflammatory cardioprotective Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in effects in rodent models of atherosclerosis and myocardial infarction, European an IL-23-dependent murine model, Proc Natl Acad Sci U S A. 114 (47) (2017) Heart Journal. 40 (2019). 12460–12465. [298] T. Ohta, M. Sugiyama, H. Hemmi, C. Yamazaki, S. Okura, I. Sasaki, et al., Crucial [279] J.J. Campbell, E.P. Bowman, K. Murphy, K.R. Youngman, M.A. Siani, D. roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in A. Thompson, et al., 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine intestinal immune homeostasis, Sci Rep. 6 (2016) 23505. expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7, [299] R. Bonecchi, G.J. Graham, Atypical Chemokine Receptors and Their Roles in the J Cell Biol. 141 (4) (1998) 1053–1059. Resolution of the Inflammatory Response, Front Immunol. 7 (2016) 224. [280] K. Jaeger, S. Bruenle, T. Weinert, W. Guba, J. Muehle, T. Miyazaki, et al., [300] B. Savino, E.M. Borroni, N.M. Torres, P. Proost, S. Struyf, A. Mortier, et al., Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Recognition versus adaptive up-regulation and degradation of CC chemokines by Receptor 7, Cell. 178 (5) (2019) 1222–1230, e10. the chemokine decoy receptor D6 are determined by their N-terminal sequence, [281] E.A. Hull-Ryde, M.A. Porter, K.A. Fowler, D. Kireev, K. Li, C.D. Simpson, et al., J Biol Chem. 284 (38) (2009) 26207–26215. Identification of Cosalane as an Inhibitor of Human and Murine CC-Chemokine [301] E.M. Borroni, C. Cancellieri, A. Vacchini, Y. Benureau, B. Lagane, F. Bachelerie, et Receptor 7 Signaling via a High-Throughput Screen, SLAS Discov. 23 (10) (2018) al., beta-arrestin-dependent activation of the cofilin pathway is required for the 1083–1091. scavenging activity of the atypical chemokine receptor D6, Sci Signal. 6 (273) [282] F. Blanco-Perez, Y. Kato, I. Gonzalez-Menendez, J. Laino, M. Ohbayashi, (2013) ra30 1-11, S1-3. M. Burggraf, et al., CCR8 leads to eosinophil migration and regulates neutrophil [302] S. Gravel, C. Malouf, P.E. Boulais, Y.A. Berchiche, S. Oishi, N. Fujii, et al., The migration in murine allergic enteritis, Sci Rep. 9 (1) (2019) 9608. peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: [283] Y. Barsheshet, G. Wildbaum, E. Levy, A. Vitenshtein, C. Akinseye, J. Griggs, et al., roles of receptor domains, J Biol Chem. 285 (49) (2010) 37939–37943. CCR8(+)FOXp3(+) Treg cells as master drivers of immune regulation, Proc Natl [303] A. Ehrlich, P. Ray, K.E. Luker, E.J. Lolis, G.D. Luker, Allosteric peptide regulators Acad Sci U S A. 114 (23) (2017) 6086–6091. of chemokine receptors CXCR4 and CXCR7, Biochem Pharmacol. 86 (9) (2013) [284] T. Oshio, R. Kawashima, Y.I. Kawamura, T. Hagiwara, N. Mizutani, T. Okada, et 1263–1271. al., Chemokine receptor CCR8 is required for lipopolysaccharide-triggered [304] S. Oishi, T. Kuroyanagi, T. Kubo, N. Montpas, Y. Yoshikawa, R. Misu, et al., cytokine production in mouse peritoneal macrophages, PLoS One. 9 (4) (2014), Development of novel CXC chemokine receptor 7 (CXCR7) ligands: selectivity e94445. switch from CXCR4 antagonists with a cyclic pentapeptide scaffold, J Med Chem. [285] P.C. Rummel, K.N. Arfelt, L. Baumann, T.J. Jenkins, S. Thiele, H.R. Luttichau, et 58 (13) (2015) 5218–5225. al., Molecular requirements for inhibition of the chemokine receptor CCR8– [305] V. Puddinu, S. Casella, E. Radice, S. Thelen, S. Dirnhofer, F. Bertoni, et al., ACKR3 probe-dependent allosteric interactions, Br J Pharmacol. 167 (6) (2012) expression on diffuse large B cell lymphoma is required for tumor spreading and 1206–1217. tissue infiltration, Oncotarget. 8 (49) (2017) 85068–85084. [286] I. Cosorich, H.M. McGuire, J. Warren, M. Danta, C. King, CCR9 Expressing T [306] R. Ameti, S. Melgrati, E. Radice, E. Cameroni, E. Hub, S. Thelen, et al., Helper and T Follicular Helper Cells Exhibit Site-Specific Identities During Characterization of a chimeric chemokine as a specific ligand for ACKR3, Inflammatory Disease, Front Immunol. 9 (2018) 2899. J Leukoc Biol. 104 (2) (2018) 391–400. [287] K.O. Arseneau, F. Cominelli, Vercirnon for the treatment of Crohn’s disease, [307] I. Kalatskaya, Y.A. Berchiche, S. Gravel, B.J. Limberg, J.S. Rosenbaum, Expert Opin Investig Drugs. 22 (7) (2013) 907–913. N. Heveker, AMD3100 is a CXCR7 ligand with allosteric agonist properties, Mol [288] B.G. Feagan, W.J. Sandborn, G. D’Haens, S.D. Lee, M. Allez, R.N. Fedorak, et al., Pharmacol. 75 (5) (2009) 1240–1247. Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as [308] M. Wijtmans, D. Maussang, F. Sirci, D.J. Scholten, M. Canals, A. Mujic-Delic, et induction therapy in active Crohn’s disease, Aliment Pharmacol Ther. 42 (10) al., Synthesis, modeling and functional activity of substituted styrene-amides as (2015) 1170–1181. small-molecule CXCR7 agonists, Eur J Med Chem. 51 (2012) 184–192. [289] N.J. Tubo, M.A. Wurbel, T.T. Charvat, T.J. Schall, M.J. Walters, J.J. Campbell, [309] B.A. Zabel, Y. Wang, S. Lewen, R.D. Berahovich, M.E. Penfold, P. Zhang, et al., A systemically-administered small molecule antagonist of CCR9 acts as a tissue- Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4- selective inhibitor of lymphocyte trafficking, PLoS One. 7 (11) (2012), e50498. mediated tumor cell transendothelial migration by CXCR7 ligands, J Immunol. [290] M.J. Walters, Y. Wang, N. Lai, T. Baumgart, B.N. Zhao, D.J. Dairaghi, et al., 183 (5) (2009) 3204–3211. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 [310] B.A. Zabel, S. Lewen, R.D. Berahovich, J.C. Jaen, T.J. Schall, The novel chemokine receptor, for treatment of inflammatory bowel disease, J Pharmacol chemokine receptor CXCR7 regulates trans-endothelial migration of cancer cells, Exp Ther. 335 (1) (2010) 61–69. Mol Cancer. 10 (2011) 73. [291] P. Bekker, K. Ebsworth, M.J. Walters, R.D. Berahovich, L.S. Ertl, T.T. Charvat, et [311] K. Yamada, N. Maishi, K. Akiyama, M. Towfik Alam, N. Ohga, T. Kawamoto, et al., CCR9 Antagonists in the Treatment of Ulcerative Colitis, Mediators Inflamm. al., CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic 2015 (2015) 628340. property, Int J Cancer. 137 (12) (2015) 2825–2836. [292] Q. Wu, J.X. Chen, Y. Chen, L.L. Cai, X.Z. Wang, W.H. Guo, et al., The chemokine [312] T. D’Huys, S. Claes, T. Van Loy, D. Schols, CXCR7/ACKR3-targeting ligands receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/ interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells, Akt pathway activation, Cell Death Dis. 9 (2) (2018) 232. Heliyon. 4 (3) (2018), e00557. [293] A. Abeywardane, G. Caviness, Y. Choi, D. Cogan, A. Gao, D. Goldberg, et al., N- [313] C. Matti, G. D’Uonnolo, M. Artinger, S. Melgrati, A. Salnikov, S. Thelen, et al., Arylsulfonyl-alpha-amino carboxamides are potent and selective inhibitors of the CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4, J Leukoc Biol. 107 (6) (2020) 1137–1154.
22