REVIEW ARTICLE published: 12 July 2012 doi: 10.3389/fimmu.2012.00175 Touch of

Xavier Blanchet 1*, Marcella Langer 1*, Christian Weber 1,2,3, Rory R. Koenen1,2 and Philipp von Hundelshausen1

1 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich, Munich, Germany 2 Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands 3 Munich Heart Alliance, Munich, Germany

Edited by: Chemoattractant cytokines or chemokines constitute a family of structurally related pro- Klaus Ley, La Jolla Institute for Allergy teins found in vertebrates, bacteria, or viruses. So far, 48 have been and Immunology, USA identified in humans, which bind to around 20 chemokine receptors.These receptors belong Reviewed by: Klaus Ley, La Jolla Institute for Allergy to the seven transmembrane G--coupled receptor family. Chemokines and their and Immunology, USA receptors were originally studied for their role in cellular trafficking of leukocytes during Tatsuo Kinashi, Kansai Medical inflammation and immune surveillance. It is now known that they exert different func- University, Japan tions under physiological conditions such as homeostasis, development, tissue repair, and *Correspondence: angiogenesis but also under pathological disorders including tumorigenesis, cancer metas- Xavier Blanchet and Marcella Langer, Institute for Cardiovascular tasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines Prevention, Ludwig-Maximilians- and chemokine receptors confer the ability to homo- and hetero-oligomerize. Many efforts University of Munich, are currently performed in establishing new therapeutically compounds able to target the Pettenkoferstrasse 9, 80336 Munich, chemokine/ system. In this review, we are interested in the role of Germany. e-mail: xavier.blanchet@med. chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular uni-muenchen.de; inflammatory diseases, the operating synergism, and the emerging therapeutic approaches marcella.langer@med. of chemokines. uni-muenchen.de Keywords: chemokine, chemokine receptor, arrest, oligomerization, vascular inflammatory diseases, leukocyte trafficking, therapeutics

INTRODUCTION than 100 genes while both pufferfish Tetraodon and Fugu genomes With the exceptions of CX3CL1/fractalkine and CXCL16/SR- contain less than 20 chemokine genes each. The PSOX,chemoattractant cytokines or chemokines constitute a fam- encompasses more than 50 different chemokine genes and pseudo- ily of small soluble signaling molecules of approximately 70 amino genes. These genes have undergone a rapid evolution in both their acid residues with a molecular weight of 7–12 kDa. In addition sequences and their family size. The conventional name is to their monomeric form, these are able to associate, still often used, which may lead to some confusion while the forming dimers, tetramers, or multimers (i.e., to oligomerize). International Union of Immunological Societies/World Health Chemokines have crucial roles in both homeostasis and dis- Organization Subcommittee on Chemokine Nomenclature has ease. Their homeostatic roles include leukocyte maturation and assigned a name to each chemokine and chemokine receptor trafficking, development, tissue repair, and angiogenesis (Ranso- (Bacon et al., 2001). A large number of human chemokine genes hoff, 2009). As disease modulators, chemokines have roles in a are known to be clustered on specific chromosomal regions. There wide variety of inflammatory and immune responses through the are two major gene clusters comprising exclusively either CXC chemoattraction of innate and adaptive immune cells. To date, or CC genes on 4q13.3-q21.1 and 17q12, respec- around 50 chemokines have been identified in humans, which tively (Table 1). These major clusters can be subdivided into two have been grouped into one of four families, CXC, CC, CX3C, and regions. For the CXC gene cluster, the regions are named GRO XC, based on the arrangement of cysteine residues involved in the and IP10 while the regions of the CC gene cluster are called formation of disulfide bonds (Table 1). In the CXC and CX3C MCP and MIP (Nomiyama et al., 2010). The GRO region con- chemokine family, one or three amino acid residues are inserted tains the CXCL1–CXCL8 genes and the IP10 region the CXCL9– between the first two of four cysteine residues, respectively. The CXCL13 genes, respectively. In the CC major cluster, the MCP first and third cysteine residues are absent in the XC subfamily and MIP regions comprise 6 and 12 genes, respectively (CCL2, that possesses only one disulfide bond. In the CC subfamily, the CCL7, CCL11, CCL8, CCL13, CCL1 versus CCL5, CCL16, CCL14, first two cysteines are juxtaposed. Another family has been recently CCL15, CCL23, CCL18, CCL3, CCL4, CCL3L3, CCL4L1, CCL3L1, described in the zebrafish genome, namely the CX family, which CCL4L2). In addition to the two major clusters, a CC “mini”- lacks one of the four cysteine residues highly conserved amongst cluster is found on chromosome 7 (comprising the CCL26 and chemokines (Nomiyama et al., 2008). All chemokines arose from a CCL24 genes), on chromosome 9 (CCL27, CCL19, CCL21), and single ancestral gene, originating approximately 650 million years on chromosome 16 (CCL22, CX3CL1, and CCL17), respectively. ago (Nomiyama et al., 2010). Amongst vertebrates, the zebrafish Both XCL1 and XCL2 are also found in a “mini”-cluster on genome has the highest number of chemokine genes with more chromosome 1.

www.frontiersin.org July 2012 | Volume 3 | Article 175 | 1 Blanchet et al. The fabulous destiny of chemoattractant cytokines 1 Cluster name Receptor Number of amino acids (mature form) Number of exons size (kb) 17q1217q1217q12 1.9017q21-q23 1.89 1.79 3 1.88 3 3 3 69 70 69 70 MIP MIP MIP MIP CCR1, CCR5, CCBP2 CCR1, CCR5 CCR5, CCBP2 CCR1, CCR5 , IMAC 7q11.2 20.22 3 71 “Mini”-CC 7 CCR3 α α ; LD78 ; LARC; Exodus-1 2q33-q37 3.72 4 70, 69 CCR6 ; ELC; Exodus-3 9p13 1.71 4 77 “Mini”-CC 9 CCR7, CCRL1, CCRL2 α β β α β β 8; MPIF-1 17q11.2 4.91 4 99, 116 MIP CCR1, FPR2 β Conventional name Chromosome Gene symbol CCL CCL24CCL25 CCL24CCL26 CCL25CCL27 Eotaxin-2; CCL26CCL28 MPIF-2 TECK CCL27 Eotaxin-3, CCL28 MIP-4 CTACK; ILC; ESKINE MEC 7q11.23 9p13 1.92 19p13.2 3 0.80 5p12 34.81 3 93 5 30.88 88 127, 61 3 “Mini”-CC 7 CCR3 108 “Mini”-CC 9 CCR10 CCR9, CCRL1 CCR3, CCR10 CCL20CCL21 CCL20CCL22 CCL21CCL23 MIP-3 CCL22 6Ckine; CCL23 SLC; Exodus-2 MDC; STCP-1; AMCD-1 CK 9p13 16q13 1.14 7.41 4 3 111 69 “Mini”-CC 9 “Mini”-CC 16 CCR7,CCRL1 CCR4, DARC, CCBP2 Name Official CCL1CCL2CCL3 CCL1CCL3L1 CCL2CCL3P1 CCL3 TCA3; CCL3L1 I-309CCL3L3 CCL3L2 MCP-1; MCAF; JECCL4 LD78 CCL3L3 MIP-1 CCL4L1 –CCL4L2 LD78 CCL4 CCL4L1CCL5 CCL4L2CCL7 LAG-1 MIP-1 CCL8 LAG-1 CCL5 17q11.2-q21.1CCL11 CCL7 17q11.2CCL13 CCL8 1.93 RANTES CCL11CCL14 MCP-3; MARC CCL13CCL15 MCP-2 Eotaxin, CCL14 2.85CCL16 3 MCP-4 CCL15CCL17 HCC-1 CCL16CCL18 17q21.1 3 HCC-2 CCL17CCL19 17q12 HCC-4; CCL18 76 LEC 17q12 TARC; ABCD-2 CCL19 – 17q11.2-q12 DC-CK1; PARC; AMAC-1 17q11.2-q12 73 MIP-3 1.80 2.01 8.88 1.80 17q21.1-q21.2 17q11.2 MCP 17q11.2 3 2.51 17q11.2 3 3 17q11.2 3 MCP 17q11.2 16q13 2.35 17q11.2 CCR2, 3 CCR3, 2.21 DARC, CCBP2 7.2 69 76 3.07 68 68 3 4.98 4.46 CCR8 11.29 3 3 74 4 3 3 4 76 MIP MIP MCP MIP 82 MIP 69 74 97 MCP 71 92 CCR5, CCR1, CCBP2 CCR2, MCP CCR3, CCR5, DARC, CCR1, CCBP2 CCR5, CCR3, CCBP2 CCR5, DARC, MCP CCBP2, CCRL2 MIP CCR3,CCR5, MIP DARC, D6 MIP “Mini”-CC MIP 16 CCR2,CCR3 CCR4, DARC, CCBP2 CCR2, CCR3, CCR5, DARC, CCBP2 DARC CCR1 CCR1 CCR1, CCR3, DARC Table 1 | Human chemokine genes.

Frontiers in Immunology | Chemoattractants July 2012 | Volume 3 | Article 175| 2 Blanchet et al. The fabulous destiny of chemoattractant cytokines CXCR6 “Mini”-CC 16 CX3CR1 2 2 gene and ,http://www.uniprot.org/ respectively. = –– – – – – 72 98 4q13.34q13.3 2.24 2.18 4 3 73 73 GRO GRO CXCR2, DARC CXCR2, DARC 22q11.23 0.84 3 114 CXCR2, CXCR4; CXCR7, CD74 10q11.1 14.94 4 681q24.2 3.23 3 93 CXCR4, CXCR7 “Mini”-CC 1 XCR1 β α ; ATAC 1q23 5.60 3 93 “Mini”-CC 1 XCR1 α ; MIP-2; KC 4q13.3 1.85 4 73 GRO CXCR2, DARC ; MIP-2 ; MIP-2 α γ β β ; MGSA- , MGSA- ; MGSA- α β γ α β γ factor, glycosylation-inhibiting factor Only agonist receptors are indicated (adaptedEach from chemokineSchall domain and of, Proudfoot ). CXCL162011 and CX3CL1 is constituted by 76 amino acids. CXC XC CX3C NOT ASSIGNED CXCL1p-CXCL1CXCL2CXCL3 CXCL1 CXCL1PCXCL4CXCL4L1 CXCL2CXCL5 CXCL3 GRO- –CXCL6 PF4 PF4V1CXCL7 GRO- p-CXCL7 CXCL5 GRO- CXCL8 CXCL6 PF4-ALT; CXCL4V1CXCL9 PF4 PPBP PPBPL1CXCL10 ENA-78CXCL11 IL8 GCP-2CXCL12 CXCL9 – NAP-2; beta-TG; CXCL10 CTAP-III CXCL11 CXCL12 MIG IL8 IP10; CRG-2 4q13.3 I-TAC, 4q13.3 SDF-1 CXCL17 4q13.3 1.18XCL1 – 4q13.3 4q13.3 CXCL17 1.75 4q13.3 4CX3CL1 DMC XCL1 4 0.92 3.05 4q13.3 3 4q21.1MIF 70 2.20 CX3CL1 4q21.1 3 4 4q13.3 Lymphotactin; SCM-1 4q21.1 81, 85, 94 2.42 – 3Human Fractalkine; gene Neurotactin; and ABCD-3 MIF protein data1 were collected from 70 78 6.02 the GRO web sitesEntrezGene: 2 3.21http://www.ncbi.nlm.nih.gov/sites/entrez?db 2.51 GRO 4 77 16q13 GRO 4 Macrophage 4 migration 4 inhibitory 77 19q13.2 GRO GRO 12.54 103 CXCR2, DARC GRO 79, 82 73 14.44 3 IP10 CXCR3 CXCR2, DARC 4 GRO IP10 GRO 355 CXCR1, IP10 CXCR2, DARC 98 CXCR3 CXCR1, CXCR2, CXCR3 DARC CXCR3, CXCR7, DARC ? CXCL12CXCL12CXCL13CXCL14 CXCL12CXCL16 CXCL12 CXCL13 SDF-1 CXCL14 SDF-1 CXCL16 BCA-1; BLCXCL2 BRAK SR-PSOX XCL2 SCM-1 4q21.1 17p13.2 5q31 100 6.39 8.60 4 5 87 4 225 77 IP10 CXCR5 ?

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Besides their structural classification, another organization of principal neutrophil β2-integrins are CD11a/CD18 (LFA-1) and chemokines has been proposed based on their expression and CD11b/CD18 (Mac-1, CR3; Luo et al., 2007) although neutrophils their functional activity. This classification groups chemokines can express p150,95/αxβ2 (CD11c/CD18) and at low level very late into three “families”: pro-inflammatory, homeostatic, and mixed antigen (VLA) 4/α4β1 (CD49d/CD18; Zarbock et al., 2012). LFA- function (Mantovani et al., 2006). Pro-inflammatory chemokines 1 and Mac-1 have been shown to mediate neutrophil adhesion by are up-regulated under inflammatory conditions and are involved interacting with ICAM-1 while αxβ2 is able to bind the N-terminal in the leukocyte recruitment to inflamed sites. Homeostatic part of the alpha chain of fibrinogen (Loike et al., 1991; Diamond chemokines are expressed constitutively at non-inflamed sites and Springer, 1993; Lum et al., 2002). During neutrophil adhesion, and are involved in homeostatic migration and homing of LFA-1 and Mac-1 appear to have sequential roles binding ICAM-1 cells in physiological conditions such as lymphocyte homing. under shear conditions (Neelamegham et al., 1998; Hentzen et al., Some chemokines have both properties, and are thus called 2000). In a two-step process neutrophils adhere first to ICAM-1 mixed-function chemokines. by interacting with LFA-1 and then Mac-1 acts as a stabilizer of Chemokines act by binding specialized receptors on the target the LFA-1/ICAM-1 bond. cell surface. These chemokine receptors are also grouped into four The transition of rolling to leukocyte arrest and activation is families, CXCR, CCR, XCR, and CX3R, based on the chemokine triggered by chemokines such as CXCL1/GRO-α while others like family they bind (Nomiyama et al., 2011). The entire group of CCL2/MCP-1 per se are rather promoting transmigration. Arrest chemokine receptors belongs to the seven transmembrane domain of rolling leukocytes is triggered by an increase in the affinity of G-protein-coupled receptors that usually combine the receptor to integrins by chemokines (Ley et al., 2007; Chavakis et al., 2009). the Gαi subunit of heterotrimeric G proteins. So far, around 25 Different cell types,such as mesenchymal stem cells,endothelial human chemokine receptor genes have been identified (Table 2). cells, and circulating blood cells including leukocytes or platelets Interestingly, 12 of these receptors are found on human chromo- produce and release a broad range of chemokines and other some 13 and stretched around 13.5 megabases. In addition, several chemoattractants that facilitate and enhance the recruitment of decoy receptors have been reported to bind chemokine ligands leukocytes. Some of these pro-inflammatory mediators circulate without eliciting signal transduction. These comprise CXCR7, in the plasma, others are only found in the inflamed tissue, and yet CCBP2, Duffy antigen receptor for chemokines (DARC), CCRL1, others are presented on endothelial cells. Furthermore, additional and CCRL2. The first chemokine receptor genes appeared in the to direct endothelial deposition from the luminal side, chemokines most primitive vertebrate, agnathan lamprey (hagfish), around are transported via caveolae through the endothelium and pre- 480 million years ago (Nomiyama et al., 2011). sented to the apical side of the cell instead of diffusing through The chemokine/chemokine receptor system can be considered endothelial cell junctions (Pruenster et al., 2009). This transcyto- as a “puzzle” since many receptors have different chemokines as sis requires the DARC (Middleton et al., 1997). Recently, a new ligands and vice versa. However, thanks to the multiple combina- mechanism has been highlighted introducing the concept of lym- tions allowed, this system offers robustness. Indeed, even if one phocyte transendothelial migration by intraendothelial vesicle- chemokine or receptor does not function, another one can replace stored chemokines beneath the apical membrane (Shulman et al., it. 2011). Chemokines bind chemokine receptors expressed on leuko- CHEMOKINES IN LEUKOCYTE TRAFFICKING AND cytes to induce activation. In addition, most chemokines are INFLAMMATORY DISEASES also able to bind extracellular matrix components, including gly- Leukocyte recruitment represents a fundamental episode during cosaminoglycans (GAGs), to get immobilized and be presented to infection, in inflammatory disorders, such as atherosclerosis, as leukocytes. This is essential in order to avoid to be swept away well as in autoimmune diseases, such as in psoriasis, rheumatoid under flow conditions from the cell surface. This coimmobiliza- arthritis, and chronic lung disease (Luster et al., 2005). Initially, tion with adhesion molecules will promote leukocyte activation, leukocyte extravasation was described as a three-step process adhesion, and migration. namely rolling, activation, and arrest. Recently, new insights have The following section will give several examples of chemokine allowed defining a more complex process by adding several steps contribution in leukocyte trafficking and in inflammatory diseases to the three original, including tethering (or capture), slow rolling, with a particular focus on vascular inflammatory diseases. adhesion strengthening, spreading, intravascular crawling, and finally paracellular and transcellular transmigration. CHEMOKINES IN PLATELETS Whereas capture and slow rolling are mediated by reversible As outlined above, activated platelets are able to release and transient interactions between E-, L-, or P-selectin and lig- chemokines as well as a battery of different mediators to modulate ands such as P-selectin glycoprotein-1 (PSGL-1), the adhesion inflammation. Thus, platelets have been found to be involved in of leukocytes to endothelial cells is mediated by the interaction different diseases with an inflammatory component such as obe- of VCAM1 and ICAM-1, receptor for advanced glycation end- sity, acute lung injury, or coronary artery disease where they inter- products (RAGE), or mucosal vascular cell-adhesion molecule act with both endothelial cells and leukocytes leading to a diversity 1 (MADCAM1) with leukocyte integrins. The common struc- of effects (van Gils et al., 2009; von Hundelshausen et al., 2009). ture of integrins is a non-covalently associated α and β subunit. Platelets release chemotactic cytokines stored in α-granules upon So far, 16 α subunits and 8 β subunits have been identified, activation. Inter alia, CXCL4/PF4, CCL5/RANTES, CXCL7/NAP- and various combinations form at least 22 heterodimers. The 2, CXCL12/SDF-1, CXCL1/GRO-α, or CXCL5/ENA-78 are able

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Table 2 | Human chemokine receptor genes.

Name Conventional name Chromosome Gene Number Number of Ligands size of exons amino acids (kb)

CXCR CXCR1 IL8R1; IL8RA; CMKAR1 2q35 4.15 2 350 CXCL6, CXCL8, CXCR2 IL8R2; IL8RB; CMKAR2 2q35 11.96 4 360 CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, MIF CXCR2P1 CXCR2P; IL8RBP – 1 CXCR3A IP10-R; MigR; CMKAR3; Xq13.1 2.60 2 368 CXCL4, CXCL4L1, CXCL9, CXCL10, CXCL11, CXCR3B IP10-R; MigR; CMKAR3; – – 2 415 CXCR3-alt – – 2 267 CXCR4 LAP3; LCR1 2q21 2.60 2 352, 356 CXCL12, MIF CXCR5 BLR1; MDR15 11q23.3 12.43 2 372, 327 CXCL13 CXCR6 BONZO; CD186 3p21.26 4.87 2 342 CXCL16 CCR CCR1 CKR1; CMKBR1; MIP1aR 3p21 6.63 2 355 CCL3, CCL3L1, CCL3L3, CCL5, CCL7, CCL14, CCL15, CCL16; CCL23, CCR2A CMKAR2; CD182; CKR2B 3p21.31 7.18 2 374 CCL2, CCL7, CCL8, CCL13, CCR2B CKR2B – – 3 360 CCR3 CKR3; CMKBR3 3p21.3 24.32 3 355 CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL24, CCL26, CCL28, CCR4 CKR4; CMKBR4; ChemR13 3p24 3.33 2 360 CCL17; CCL22 CCR5 CMKBR5; CKR5 3p21.23 6.06 3 352 CCL3, CCL3L1, CCL3L1, CCL4, CCL4L1, CCL4L2, CCL5, CCL7, CCL11, CCL13 CCR6 BN-1; DCR2; CKR-L3 6q27 27.33 3 374 CCL20 CCR7 BLR2; CMKBR7; EBI1 17q12-q21.2 11.71 3 378 CCL19, CCL21 CCR8 CKRL1; CMKBR8; CMKBTER1 3p22 3.97 2 355 CCL1 CCR9A GPR-9-6; GPR28 3p21.3 16.67 4 359 CCL25 CCR9B GPR-9-6; GPR28 – – – 357 CCL25 CCR10 GPR2 17q21.1-q21.3 2.42 2 362 CCL27, CCL28 XCR XCR1 CCXCR1; GPR5 3p21.3 7.68 2 333 XCL1, XCL2 CX3CR CX3CR1 CMKDR1; GPR13; CCRL1 3p21.3 18.24 4 355, 387, 362 CX3CL1 DECOYRECEPTORS CXCR7 RDC1; GPR159 2q37.3 12.61 2 362 CXCL11, CXCL12, MIF CCRL1 CCR11; CCBP2; VSHK1; CCX- 3q22 5.29 2 350 CCL19, CCL21, CCL25 CKR; PPR1 CCRL1P1 dJ509I19.4 6q23.3 1 CCRL2 CKRX; CRAM-A; CRAM-B; HCR 3p21 2.29 3 344, 256 CCL5, CCL19 CCBP2 D6 3p21.3 57.81 3 384 CCL2, CCL3, CCL4, CCL4L1, CCL4L2, CCL5, CCL7, CCL11, CCL13; CCL17, CCL22, DARC Duffy; FY 1q21-q22 2.48 2 336, 338 CCL2, CCL5, CCL7, CCL11, CCL13, CCL15, CCL17, CCL18, CCL22, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL11 FORMYL PEPTIDE RECEPTOR FPR2 FPRL1; LXA4R; FMLP-R-II; 19q13.3-q13.4 9.33 3 351 CCL23, Lipoxin A4, serum amyloid A, β amyloid FMLPX; FPR2A; FPRH1 peptide Aβ42, SAA, MMK, Hp-(2-20)

Human gene and protein data were taken from the web sitesEntrezGene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene and http://www.uniprot.org/, respectively. to mediate the endothelial adhesion of different cells including Platelets secrete CXCL4 which is the first and most abun- monocytes, neutrophils, and progenitor cells (Lievens and von dant chemokine identified in releasates from activated platelets Hundelshausen, 2011). and which is involved in a wide range of physiological processes

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such as proliferation and angiogenesis. This chemokine is also content of lesions (von Hundelshausen et al., 2005; Koenen et al., involved in numerous pathological processes. High levels of 2009). CXCL4 are positively correlated with Crohn’s disease activity index A non-allelic variant form of CXCL4, called CXCL4L1 or (Simi et al., 1987). In Heparin-induced thrombocytopenia (HIT), PF4ALT which differs only in three amino acids in the C-terminal autoantibodies developed against high molecular complexes of α-helix of the protein has been identified in different kind of CXCL4/heparin or CXCL4/GAG side chains. The presence of HIT cells including leukocytes, endothelial, or smooth muscle cells antibodies can lead to platelet activation and depletion through (Lasagni et al., 2007). CXCL4L1 is capable of inducing endothelial platelet consumption in venous thrombosis (Greinacher, 2009). cell chemokinesis and has been characterized as a potent anti- CXCL4 exerts chemotactic activities on different cells includ- angiogenic regulator similar to CXCL4. Important differences of ing neutrophils, monocytes (Deuel et al., 1981), and activated CXCL4L1 and CXCL4 are a lower affinity for CCL5 (Sarabi et al., T-lymphocytes in a pertussis toxin-sensitive manner (Mueller 2011) and GAGs, e.g., heparin (Dubrac et al., 2010). Substanti- et al., 2008). Recently, CXCL4 has also been shown to be able ating the role of CCL5–CXCL4 heterodimers CXCL4L1 failed to to induce a specific macrophage type with specific phenotypic increase CCL5-triggered monocyte adhesion (Sarabi et al., 2011). and functional characteristics (Gleissner, 2012). Moreover, it pro- The decreased affinity of CXCL4L1 compared to CXCL4 may have motes adhesion of neutrophils on endothelial cells (Petersen et al., critical implications for cell adhesion since CXCL4L1 will not be 1999). Although CXCL4 has been reported to bind to and stimu- retained at its site of expression. The existence of heparan sulfate in late CXCR3 and a splice variant thereof (CXCR3B), the functional the subendothelial extracellular matrix has been found to regulate importance of these two receptors for the biological activity of the arrest function of CCL5 and CCL4/MIP-1β (Gilat et al., 1994). CXCL4 is not clear. For instance, a recent report found CXCL4 On the endothelial surface under flow conditions, both platelet- to be involved in ligand driven monocyte down-regulation of derived and recombinant CCL5 are able to bind to activated chemokine receptors CCR1, CCR2, and CCR5 by releasing the endothelium and to trigger the firm arrest and transmigration respective ligands (CCL2-4) from CXCL4-activated monocytes in of monocytes (von Hundelshausen et al., 2001). absence of CXCR3 highlighting the connection between platelets Moreover, the oligomerization of CCL5 is crucial for CCR1- and monocytes (Schwartzkopff et al., 2012). CXCL4 can induce mediated leukocyte arrest on inflamed endothelium but not for exocytosis and firm neutrophil adhesion to endothelium when their transmigration via CCR5 (Baltus et al., 2003). In bronchial incubated with the appropriate co-stimuli. A contribution of mucosa of patients with chronic obstructive pulmonary disease CXCL4 in cardiovascular diseases has been described in both (COPD), CCL5, and to a lesser extent CXCL7, have been found human and mouse where CXCL4 has been found in the endothe- to be the most abundant chemokine expressed in the bronchial lium, neovasculature, macrophages, and calcified regions of ath- epithelium and are associated with an increase of neutrophil erosclerotic carotid arteries (Pitsilos et al., 2003). Moreover, a activation (Di Stefano et al., 2009). strong positive correlation between both luminal and neovas- CXCL12 or SDF-1α,which is the ligand for CXCR4 and CXCR7, cular CXCL4 staining and coronary artery disease and between has both proatherogenic and antiatherosclerotic properties (Weber CXCL4 in macrophages and the presence of symptomatic ath- et al., 2011). Blocking the CXCR4–CXCL12 axis leads to a release erosclerotic disease has been found. In a murine model of ath- of different leukocyte subsets into the circulation. In this context, erosclerosis, the knock-out of CXCL4 has been shown to exert monocytosis and neutrophilia are conditions positively correlated an atheroprotective effect reducing atherosclerotic lesion forma- with the development and severity of atherosclerosis. On the other tion (Sachais et al., 2007). Activation of platelets results in a hand has CXCL12 been demonstrated to be crucial for the healing release of stored-P-selectin -CXCL4 and CCL5 from granules. of arterial lesions by the regenerative capacity of progenitor cells CCL5 has been detected on the luminal surface of atheroscle- which are attracted to adhere be CXCL12 (Massberg et al.,2006). In rotic murine and human carotid arteries or neointimal lesions addition to its production by platelets, CXCL12 is expressed in the after arterial injury and can be deposited on inflamed or ather- bone marrow and in cells directly relevant to atherogenesis,includ- osclerotic endothelium by activated platelets, thereby triggering ing endothelial cells, smooth muscle cells, and leukocytes, which monocyte recruitment under flow (von Hundelshausen et al., enables it to regulate the trafficking and localization of imma- 2001; Schober et al., 2002). The deposition of platelet chemokines ture and maturing leukocytes, including bone marrow stem cells, can be facilitated by platelet-derived microparticles (Mause et al., neutrophils, T cells, and monocytic cells (Abi-Younes et al., 2000; 2005). Injection of activated platelets into the tail vein of athero- Zeiffer et al., 2004; Stellos et al., 2009). Furthermore, CXCL12 has sclerosis prone mice results in exacerbated atherosclerotic lesions been thought to play a pro-inflammatory role in various autoim- and increased endothelial deposition of CXCL4 and CCL5 depen- mune diseases, especially in rheumatoid arthritis and nephritis, in dent on the presence of P-selectin (Huo et al., 2003). Therefore, murine lupus erythematosus as well as in ongoing experimental platelet adhesion molecules such as P-selectin are mediating tran- autoimmune encephalomyelitis (Meiron et al., 2008; Karin, 2010). sient interactions with endothelial cells enabling a local delivery of Recently, changes in CXCL12 signaling patterns have been found soluble chemokines. We have discovered that heterophilic inter- to be necessary for bone marrow neutrophil mobilization and are actions between CXCL4 and CCL5 (see below) are responsible involved in polymicrobial sepsis, where its inhibition resulted in for enhanced monocyte recruitment into the arterial wall which peritoneal cavity neutropenia (Delano et al., 2011). While both explains to a certain extent why activated platelets are strong CCL5 and CCL7/MCP-3 are able to activate and to induce the promoters of atherosclerosis. Peptides inhibiting the association chemotaxis of eosinophil and basophil granulocytes in allergy of CXCL4 and CCL5 decrease atherosclerosis and macrophage (Baggiolini and Dahinden, 1994), CCL11/Eotaxin has been found

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to be a powerful attractant for eosinophils and has also been iden- gradient with a long gradient and effective range for leukocyte tified in atherosclerotic lesions (Baggiolini et al., 1997; Haley et al., recruitment. 2000). CXCL8/interleukin-8/IL8 has been found in intracellular gran- The expression of CXCL7 is restricted to the platelet-lineage. ules from skin mast cells and mast cell lines (Möller et al., 1993). Proteolytic cleavage of the carboxy-terminal part of pro-platelet Recently, Kim et al.(2010) have shown that CXCL8 synthesis is basic protein (PPBP) and the proteolytic removal of the N- induced via the leukotriene B4/leukotriene B4 Receptor 2 path- terminal part of PPBP produces two other chemokines namely way in response to IL-1β in human primary mast cells and mast connective tissue-activating peptide III (CTAP-III) and beta- cell line HMC-1. CXCL8 released by mast cells is implicated in thromboglobulin (beta-TG; Walz and Baggiolini, 1990; von Hun- the selective chemotaxis of CXCR1-expressing natural killer cells delshausen et al., 2007). Dependent on CXCR2, CTAP-III, and (Burke et al., 2008). CXCL8 also induces neutrophil migration CXCL7 promote neutrophil and monocyte adhesion to human and activation by binding to G-protein-coupled receptors on their endothelial cells under flow conditions, respectively (Schenk et al., surface, namely human CXCR1 and CXCR2 (Wuyts et al., 1998). 2002; Baltus et al., 2005). The chemotactic potential of CXCL7 is During inflammation, CXCL8 is produced and presented to the also enhanced in COPD patients (Traves et al., 2004). endothelial surface in association with GAGs. In a recent study, CXCL5/ENA-78 has been shown to act as a potent chemoat- using obligate monomeric and dimeric IL8 mutants, the oligomer- tractant and activator of neutrophil function via CXCR2 (Ahuja ization state of CXCL8 was shown to have an influence on the and Murphy, 1996). CXCL5 has also been found to be strongly kinetics of the neutrophil extravasation. The dimeric form ini- correlated with the number of neutrophils in patients with acute tiated a fast robust but short lived vascular efflux whereas the respiratory distress syndrome (Goodman et al., 1996). monomeric form resulted in a weaker but longer-lasting response During early atherosclerosis, CXCL1/GRO-α immobilized on (Das et al., 2010). Also, this chemokine is among the most impor- the surface of endothelial cells via heparin proteoglycans induces tant in the recruitment of inflammatory cells, mostly neutrophils, the firm adhesion of rolling monocytes expressing CXCR2 in COPD (Barnes, 2004). (Schwartz et al., 1994; Huo et al., 2001; Boisvert et al., 2006). More- over, a recent study has shown that in vivo, lysophosphatidic acid CHEMOKINES IN DENDRITIC CELLS: CCL17 AS EXAMPLE increased the progression of atherosclerosis and recruited leuko- CCL17/TARC (thymus and activation regulated chemokine) cytes to the vessel wall during early atherogenesis via lysophospha- together with CCL22/MDC (macrophage-derived chemokine) are tidic acid receptor-mediated release of endothelial CXCL1 (Zhou expressed in relevant amounts by mature dendritic cells but occur et al., 2011). A study conducted on elderly COPD patients has also as well in other cell types such as fibroblasts. CCL17 is constitu- indicated that CXCL1 might be a relevant candidate biomarker for tively expressed in the thymus (Saeki and Tamaki, 2006). CCL17 this disease (Tsai et al., 2010). is a ligand for CCR4, which is predominantly expressed on Th2 lymphocytes, basophils, and natural killer cells. Recently, dendritic CHEMOKINES IN MAST CELLS cell-derived CCL17 has been found to be critical in atherosclero- In addition to their role as sentinels in the recognition of sis (Weber et al., 2011). Indeed, deficiency of CCL17 in Apoe−/− pathogens, mast cells (like platelets) are able to communicate mice results in a reduction of the plaque formation in aortic root with immune cells facilitating the recruitment of leukocytes to since CCL17 inhibits the expansion of atheroprotective Tregs and sites of infection. Indeed, mast cells are able to produce different attracts CD4+ and CD3+ T cells. chemokines including CCL4, CXCL8, or CCL11 assisting in the recruitment of CD8+ T cells, eosinophils, and natural killer cells, MEMBRANE-BOUND CHEMOKINES respectively (Abraham and St John, 2010). In addition to different types of cells such as T cells, macrophages, CCL3/MIP-1α and CCL4/MIP-1β can initiate diverse cellu- cytokine-induced smooth muscle cells, and endothelial cells, lar responses that regulate both acute and chronic inflamma- CXCL16/SR-PSOX has been recently identified for the first time in tion via their interaction with CCR1 and CCR5. In addition, platelets (Seizer et al., 2011). This protein constitutes an atypical proteoglycan-bound CCL4 is used to effectively activate and chemokine because it is expressed as a cell surface bound molecule induce the adhesion of circulating lymphocytes for their extrava- but is also found in a soluble form after shedding. CXCL16 has also sation through lymph node endothelium (Tanaka et al., 1993). been involved in different diseases. Thus, a low plasma concentra- The quaternary structures of CCL3 and CCL4 are decisive for tion of CXCL16 has been associated with coronary artery disease their biological activity. Aggregation of CCL3 and CCL4 can be and has been found in atherosclerotic lesions in human and mice considered as polymerization processes of MIP-1 dimers, which (Wuttge et al., 2004; Sheikine and Hansson, 2006). In vivo and constitute the basic unit of MIP-1 proteins. MIP-1 monomers in vitro, homocysteine, a homolog of cysteine that can promote form dimers of the CC-type by creating an anti-parallel β-sheet atherosclerosis (Harker et al., 1976), has been found to stimulate of the N-termini (Lodi et al., 1994; Czaplewski et al., 1999; CXCL16 production and deposition on the surface of endothelial Ren et al., 2010). MIP-1 dimers associate to polymers consist- cells via both production of ROS and a PPARγ-dependant path- ing up to 50 units forming a double helixed rod like structure. way, thereby increasing adhesion of lymphocytes to endothelial Polymerization of MIP-1 protects MIP-1 from proteolytic degra- cells (Postea et al., 2008). dation while the positively charged region of MIP-1, which is Like CXCL16, CX3CL1 is an atypical multimodular chemokine crucial for the receptor binding, is buried. The continuous and that exists both in a membrane-tethered or soluble form. The slow release of monomers from the polymer leads to a shallow immobilized form consists of a chemokine domain anchored to

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the plasma membrane through an extended mucin-like stalk, cells that have extravasated in response to subendothelial CCL5 a transmembrane helix, and an intracellular domain. Besides, may intravasate after exposure to subendothelial CXCL12 under CX3CL1 has an anti-apoptotic and a proliferative effect on smooth flow conditions. High concentration of a chemokine, as already muscle cells (White et al., 2010). Previous data have shown that observable in the typically bell shaped response upon increasing CX3CL1 could serve as an adhesion molecule (Fong et al., 1998; chemokine concentration, is an important factor. However the Goda et al., 2000). However, more recent data indicated that, exact molecular mechanisms of chemokine-induced chemorepul- although CX3CL1 might mediate leukocyte adhesion, this phe- sion are still ill defined. Using a CXCL12 model, Zlatopolskiy and nomenon occurred only under low shear force and not under Laurence(2001) postulated that chemokine-mediated repulsion physiological conditions (Kerfoot et al.,2003). Regarding endothe- would be triggered by an excess of free ligand in the vicinity of lial cells, CX3CL1 is expressed on the surface of IFN-γ/TNF-α- the cell that would lead to a dimerization of the receptor, followed activated HUVEC and promotes leukocyte adhesion to athero- by an internalization of the ligand/receptor complexes. Internal- sclerotic mouse arteries in vivo and under arterial flow in vitro. ization, digestion of the ligand, and recycling of the receptors More precisely, CX3CL1 expressed by inflamed endothelial cells is would be realized under the same way than during the chemoat- recognized by CX3CR1 on activated platelets. Ligation of platelet traction process. The difference would take place through the CX3CR1 results in platelet activation and subsequent exposure localization of the recycled receptors. The reappearance of the of P-selectin on the surface of adherent platelets (Schulz et al., internalized receptors may occur not on the apical side of the cell 2007). The inflamed CX3CL1-expressing endothelial cells can also but on the basal side resulting in a reverse movement. Summa- recruit the non-classical subset of monocytes which highly express rizing, the gradient dependent direction of a chemokine triggered CXC3CR1 (Geissmann et al., 2010). Under homeostatic condi- movement is concentration dependent. Thus, at least two differ- tions, the disruption of the CX3CL1–CX3CR1 axis leads to a ent signaling pathways have to exist at the beginning, converging specific reduction of circulating non-classical monocytes in mice later again to reorganize the cytoskeleton for cell polarization and (Landsman et al., 2009). Addition of full-length recombinant sol- movement. Possible explanations for the chemorepulsion at high uble CX3CL1 to human monocytes has also shown to decrease concentrations and chemoattraction at low concentrations are apoptosis triggered by serum deprivation or treatment with 7-β- the chemokine dimerization at high concentrations, high- and hydroxycholesterol. This reduction of apoptosis occurred in both low-affinity binding sites for chemokines on their cognate recep- CX3CR1-expressing CD14++CD16− and CD14+CD16+ mono- tor, rapid recycling of GPCRs, apical rearrangements of recycled cyte subsets. However, the precise mechanism is still unclear. A GPCRs, the oligomerization or homodimerization of GPCR with recent study shows that platelets over-expressing CX3CR1 on their receptor and non-receptor proteins, and allosteric mechanisms. surface are recruited alone or in association with monocytes to the site of inflammation. This phenomenon might contribute to an GENETIC VARIATIONS IN CHEMOKINE GENES acceleration of atherosclerotic lesions (Postea et al., 2012). Different studies have been carried out in order to evaluate the relationship between chemokine/chemokine receptor genes CHEMOREPULSION and inflammatory diseases including cardiovascular diseases. Another aspect to take into consideration in the involvement of Table 3 provides several examples illustrating the association of chemokines in leukocyte trafficking is the fact that chemokines chemokine/chemokine receptor polymorphisms with cardiovas- could favor a“flight” of leukocytes from a tissue to reach the blood cular diseases. circulation or another tissue. In this case, leukocytes might run In order to identify genes involved in cardiovascular diseases away from a chemokine gradient. This reverse migration from a and before the emergence of genome-wide association studies peak concentration of chemokine is named chemorepulsion or (GWAS), many efforts have been undertaken with gene candidate fugetaxis. However, chemorepulsion refers more to a mediator studies. In these studies several chemokine or chemokine receptor that, depending on its concentration, can either repel or recruit gene candidates have been found to be associated with cardio- cells using the same receptor. This phenomenon has been com- vascular diseases. For instance, a polymorphism in the promoter prehensively studied in the context of T-cell trafficking during the region of the CCL5 gene called rs2107538 has been found associ- process of thymic emigration and for which an extensive review ated with coronary artery disease (Simeoni et al., 2004). However, has been recently published (Bunting et al., 2011). It has been an extensive analysis based on the MONICA/KORA Augsburg suggested that chemorepulsion could participate in the thymic Case-Cohort, Athero-Express, and CARDIoGRAM Studies has egress of human thymocytes. Thus,high concentration of CXCL12 been recently carried out. Though an association between high has been shown to repulse human single positive thymocytes CCL5 levels and an unstable plaque phenotype has been found, no in vitro and this “run away” could be abolished using a neutral- associations of either CCL5 serum levels or its content in carotid izing CXCL12 antibody (Poznansky et al., 2000). Moreover, this plaques or its different genotypes with CAD or other coronary chemokine has also been shown to be a chemorepulsive agent of events has been established (Herder et al., 2011). The result of this firm adhesion to activated pancreatic islet microvascular endothe- study suggests that CCL5 protein levels and its gene variants might lium for both diabetogenic CD4 and CD8 T cells from NOD/LtJ not be considered as biomarkers for the risk of coronary events in mice. This repulsion results in a decrease of T-cell integrin acti- humans. As discussed by Altshuler et al.(2008), studies of can- vation in a CXCR4-independent manner (Sharp et al., 2008). didate genes are performed on specific variants that have a small Using a modified flow chamber containing a transwell insert on a priori probability of being disease-causing. Those studies are also which HUVECs are cultured, Lee et al.(2009) have shown that T able to generate false positives due to the lack of knowledge of the

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Table 3 | Examples of chemokine/chemokine receptor single nucleotide polymorphisms (SNP) associated with cardiovascular diseases.

Gene SNP Associated with p-Value References

CCL2 rs1024611 Myocardial infarction 0.005 and 0.009a McDermott et al.(2005) <0.001 and 0.001b Coronary artery disease <0.005 Szalai et al.(2001) CCL5 rs2107538 Acute coronary syndrome 0.0073 Simeoni et al.(2004) Coronary artery disease 0.0038 CCL11 rs1129844 Myocardial infarction 0.012 and 0.008c Zee et al.(2004) CXCL5 rs352046 Acute coronary syndrome 0.005 Zineh et al.(2008) CXCL8 rs4073 Acute coronary syndrome 0.004 Zhang et al.(2011) CXCL12 rs1746048 Myocardial infarction (early onset) 1 × 10−8 Kathiresan et al.(2009) Atherosclerosis severity and progression 0.009 Kiechl et al.(2010) Coronary artery disease 3 × 10−10 Schunkert et al.(2011) rs1801157 Myocardial infarction 0.007 Luan et al.(2010) rs501120 Coronary heart disease 1.4 × 10−6 Franceschini et al.(2011) Myocardial infarction 0.002 Qi et al.(2011) Coronary artery disease 9.46 × 10-8 Samani et al.(2007) CCR2 rs1799864 Heart failure 0.015 Ortlepp et al.(2003) Myocardial infarction 0.007 Ortlepp et al.(2003) 0.054d Petrkova et al.(2003) rs34948438 Myocardial infarction 0.0013e Karaali et al.(2010) 0.0016f CCR5 rs333 Myocardial infarction 0.001 Kallel et al.(2012) 0.0013 Karaali et al.(2010) Severe calcific aortic stenosis 0.037g Ortlepp et al.(2004) Myocardial infarction 0.003h Singh et al.(2012) CX3CR1 rs3732379 Coronary artery disease 0.03 McDermott et al.(2001) Acute coronary syndrome 0.001 Moatti et al.(2001) Single in-stent restenosis 0.006 Niessner et al.(2005) Recurrent in-stent restenosis 0.011 Myocardial infarction 0.006i Singh et al.(2012) aIn multivariable adjustment and multivariable adjustment of pooled-sex cohort, respectively. bIn multivariable adjustment and multivariable adjustment of male cohort, respectively. cIn an age and smoking and body mass index, hypertension, diabetes, and randomized treatment assignment adjusted recessive model of inherence, respectively. dIn female cohort. eIn patients carrying CCR5 rs34948438 wildtype (wt)/deletion (∆) genotype. fIndividuals carrying the CCR5 rs34948438 heterozygote or homozygous variant genotype (∆/∆ + wt/∆). gIn patients carrying the CCR5 rs333 SNP or CTGF -447C allele. hIn individuals carrying both CCR5 rs1799987 and rs333 SNPs. iIn individuals carrying both CX3CR1 rs3732378 and rs3732379SNPs. genetic background of cases and controls. This could explain the and directed response. There is evidence that the activity of low reproducibility in candidate gene studies and lack of recovery chemokines can be modulated by posttranslational processing between GWAS and candidate gene studies. (reviewed by Proost et al., 2003) and synergistic cytokines, e.g., Amongst the different GWAS for cardiovascular disease per- IFN-γ (Mortier et al.,2011). Especially at the early phase of inflam- formed during the last years, chemokine CXCL12 gene polymor- mation the concentration of a specific chemokine might not be phisms have been associated with CAD (e.g., Samani et al., 2007; high enough for a sufficient cell response. Hence synergism would Kathiresan et al., 2009; Franceschini et al., 2011; Schunkert et al., aid to speed up the chemokine-induced response of leukocyte 2011). In addition, the study conducted by Mehta et al.(2011) migration and to increase combinatorial specificity (Gouwy et al., found the CAD risk 10q11 to regulate the level of CXCL12 2005; Paoletti et al., 2005). A mixture of low concentrated indi- transcripts. vidual synergizing chemokines behaves like the receptor agonist at an adequate concentration. Although the synergism of some CHEMOKINE SYNERGISM BY HETEROMERIZATION single chemokines has been explored, so far a complete overview The regulation of chemokine activity during initiation and devel- how many chemokines are involved is still elusive. It was previ- opment of inflammatory diseases is crucial to reach a fast ously shown that chemokine receptor induced chemotaxis may be

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enhanced by addition of chemokines which have per se no effect augmented CCR2 response to recruit monocytes (Kuscher et al., are not cognate ligands of the respective receptor and are called 2009). Interestingly the induced monocyte recruitment by CCL7 is synergy-induced chemokines (Paoletti et al., 2005). Currently it enhanced 100 times by CCL19 and CCL21 whereas CCL2 showed is still unclear how this effect may be mediated in detail. Several less synergistic activity. By comparing a specific motif, compris- underlying mechanisms are conceivable and can depend mainly on ing five amino acids in the first β-strand of all four chemokines, the respective chemokine partners and their receptors. It is possible it has further been shown that CCL7 and CCL21 exhibit more that homeostatic and inflammatory chemokines that exhibit a dif- positively charged amino acids which correlates with a higher ferent functional activity can form heteromers and act together in a synergistic effect confirming the importance of the first β-strand. synergistic way. Furthermore the signaling of GPCR-agonists can Synergism of chemokines by heteromerization was also shown for be enhanced by non-ligand CXC- and/or CC-type chemokines. other chemokines (Paoletti et al., 2005; Allen et al., 2007; Koenen Additionally, the GPCR-agonist mono and dimer equilibrium may et al., 2009). The authors suggest that heteromers of synergisti- regulate the signaling of the specific GPCR, which results in a dif- cally acting chemokines lead to a high affinity conformation of ferent recruitment pattern of the target cells (Drury et al., 2011). the respective receptor. Another study (Venetz et al., 2010) showed It is of strong interest how the chemokine–chemokine interac- that heteromerization of CXCL12 with the inflammatory CXCR3- tions occur in vivo but it is difficult to find feasible approaches agonist CXCL9 results in a higher response of CXCR4-expressing for a direct observation of the processes in living organisms. Some T cells and malignant B cells on tumor vasculature. examples for a chemokine–chemokine synergism are given in the next parts. ANTAGONISM BY CHEMOKINE DIMERS Even if the neutrophil migration toward CXCL8 is enhanced by CHEMOKINE HETEROMERIZATION different CXC- and also CC-chemokines, i.e., CCL2 and CXCL12, Interaction between receptor agonist and non-ligand chemokines the dimerization of CXCL8 decreases its binding to CXCR1 (Fer- influences the activity of the chemokine receptor. All chemokines nando et al., 2004; Weber and Koenen, 2006). This effect might not exhibit a typical tertiary structure homology which consists of a be due to structural change but rather to a loss of conformational disordered N-terminus followed by three anti-parallel β-strands flexibility which leads to a low-affinity configuration. Thus the and the C-terminal α-helix. The quaternary structures of CC dimer is not competent enough to bind the receptor N-domain. and CXC chemokines are different. Whereas the CXC-type forms Moreover, heteromerization of CXCL8 with CXCL4 reduces the dimers with a central β-sheet, the CC-type dimerizes through the chemotactic propensity of CXCL8 (Dudek et al., 2003). These interaction of both N-termini. In case of CC- and- CXC-type heterodimers enhance the anti-proliferative effect of CXCL4 on heteromers it is difficult to predict the proper structure. Our work- endothelial cells in culture, and the CXCL8-induced migration group previously showed the synergistic interaction of CXCL4 and of CXCR2 transfected Baf3 cells as well (Nesmelova et al., 2005; CCL5 to accelerate atherosclerosis by triggering monocyte arrest Weber and Koenen, 2006). Inhibition of CXCL8-induced mono- on endothelium (von Hundelshausen et al., 2005; Koenen et al., cyte arrest is evoked by CXCL4. This effect might also be due to 2009). The synergistic effect is based on the heteromerization of a less flexible CXCL8 molecule that has a lower affinity for its these two chemokines, since peptides disrupting the heteromers receptor. However, the availability of the monomer-dimer equi- abolish this synergism. Interestingly, the quaternary structure of librium of CXCL8 is crucial to regulate tissue-specific neutrophil the CCL5–CXCL4 complex features a CC-type heteromer, which recruitment given that the recruitment profile differs due to altered exhibits paired N-termini, yet results in better receptor activation. GAG-binding interaction (Gangavarapu et al., 2012). The response to CCR4 in skin-homing T-lymphocytes is Recently, it could be shown that a monomeric or dimeric state enhanced by co-expressed chemokines in the inflamed skin. For of CXCL12 plays a crucial role for the CXCR4 activation and its example the CXCR3-agonist CXCL10 enhances the chemotaxis of mode of signaling (Ray et al., 2012). The dimeric CXCL12 activates CCR4-transfected preB-cells and T cells due to interaction with the recruitment of β-arrestin 2 to CXCR4 and chemotaxis of CXCR4- CCR4-agonist CCL22 (Sebastiani et al., 2005). Further enhance- expressing breast cancer cells, whereas the monomeric CXCL12 ment of the CCR4 activity evolves from the direct interaction of promotes the CXCR4 signaling through Gαi and Akt. Further- CCL22 with the CCR7-agonist CCL19. In addition, CCL22 was more, another recent study (Drury et al., 2011) demonstrated that also shown to interact with the CCR3-agonist CCL7. In this last monomeric CXCL12 compared with the dimeric variant exhibits case, it was shown that a sequence of five amino acids of the first β- more contact sites for CXCR4 and thus results in different receptor strand from CCL7, which contains two positively charged arginine signaling. To our knowledge it has not been tested, but supposedly residues, is needed to synergize with CCL22 and hence increases a different or even inverse activity, e.g., the chemorepellent activ- the CCR4 activation. In the same study a CCL4–CCL7 chimera ity of higher concentrated CXCL12, may well be dependent on the lost the synergetic activity, being generated by substituting the preponderance of CXCL12 dimers. first β-strand of CCL7 with that of the non-synergizing CCL4, Not only chemokine heteromerization may influence receptor lacking the positively charged amino acids. Thus the first β-strand driven signal transduction but as well the homooligomeric state of a chemokine, containing positive and hydrophilic amino acids, changes the biological activity by either buried receptor bind- seems to have a crucial role in synergism and heteromer formation. ing sites, e.g., in polymeric MIP-1 or the different kinetics of Furthermore monocyte recruitment is enhanced by the home- monomeric versus dimeric CXCL8. These insights will be helpful ostatic chemokines CCL19 and CCL21 which are both CCR7- to develop specific drugs interfering with oligomerization motifs agonists. They synergize with CCL7 and CCL2 that result in an thereby suppressing or enhancing desired chemokine effects.

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BINDING TO GPCRs THERAPEUTICS In order that chemokine–chemokine partners unfold synergism GPCRs as therapeutic targets have been reviewed extensively (Rek it is suggested that first chemokine heteromers form and sub- et al., 2009; Koenen and Weber, 2010b, 2011; Bennett et al., 2011; sequently receptor binding follows. Besides the formation of a Schall and Proudfoot, 2011; Kanzler et al., 2012). A lot has already heteromeric chemokine complex, the binding to a receptor is been done and it is still in progress to find appropriate therapeutic required to mediate the synergistic effects. GAGs, as co-receptors drugs, particularly for the prevention and treatment of HIV. Since of GPCRs, can also induce heteromerization of chemokines chemokines and the subsequent receptor signaling are involved in (Crown et al., 2006). In addition, it is speculated that instead of many diseases, there is hope that good antagonists will increase heteromerization, as mentioned above, different receptor binding the means to treat them. sites for CCL2 and CCL7 are responsible for the synergistic activ- The different interactions between chemokines, which result ity as it was previously shown for CXCR3-agonists (Colvin et al., in a changed biological activity, can be used to find new targets 2004). against inflammatory diseases. There are several possibilities for Homeostatic chemokines like CCL21, CCL19, CXCL12, and therapeutically targeting chemokines involved in inflammation. In CXCL13 are synergizing to promote a regulated lymphocyte traf- the next part, several examples are illustrating how to alter inflam- ficking across the lumen or basal lamina of high endothelial matory properties by blocking heterophilic interactions, multiple venules (HEVs) in lymph nodes. For example, CXCL12 augments chemokine axes, direct blocking of chemokine receptors as well as through its receptor CXCR4 the CCR7-induced chemotaxis of blocking of GAG-binding sites. T cells and therefore helps to transfer them across the HEVs without direct interactions with the CCR7-ligands CCL19 and MODIFIED CHEMOKINES CCL21 (Bai et al., 2009). Here the signaling through CXCR4 Modifying the target chemokine is one option to create antago- has a major impact because in T cells, deficient in CXCR4, nists since changing the molecular structure leads to a different no cooperative effect was observed. The synergistic effect is binding pattern and receptor response. Especially the N-terminal merely evident at suboptimal concentrations of the CCR7-ligands part is crucial for receptor signaling and thus a change in this CCL19 and CCL21. In summary, CXCL12–CXCR4 signaling has domain can lead to alteration or loss of receptor activation. Vari- the ability to cause a maximal T-cell response by a subopti- ants of chemokines with an extended or modified N-terminal part mal CCR7-ligand concentration. A similar observation was also are for example N-methylated CCL5 (Met-RANTES) or amino- previously shown for CXCL13 (Paoletti et al., 2005; Bai et al., oxypentane-RANTES which block the CCL5 receptors CCR1, 2009). However, it is remarkable that the heteromerization of CCR3, and CCR5 (Proudfoot et al., 1996; Elsner et al., 1997; CXCL13 with CCR7-ligands is thought to be the responsible mech- Proudfoot et al., 1999; Veillard et al., 2004). In liver fibrosis anistic reason for synergism, whereas synergy of CXCL12 with and atherosclerosis it was shown that inhibiting CCL5 receptors CCR7-ligands is independent of direct chemokine–chemokine through Met-RANTES was sufficient to reduce inflammation in interaction. In fact, it is assumed that CXCL12 increases the mice (Veillard et al., 2004; Berres et al., 2010). This phenomenon CCR7-signaling by ERK phosphorylation and actin polymer- was observed in vivo and in vitro. Another example is R6H-CXCL8, ization in T cells (Bai et al., 2009). A similar conclusion was a variant of CXCL8 with substitutions on the conserved ELR-triad provided by van Damme’s group who showed that the syner- and CXC-motif which exclusively activates CXCR1 without effect- gism of CXCL8 or CXCL12 with CCL2 is mediated through ing CXCR2. This is based on a distinct CXCL8 binding mechanism: CXCR1/2 (CXCL8) and CXCR4 (CXCL12; Gouwy et al., 2008, the CXCR2 activation is mediated by the N-terminal ELR- and 2009). When the concentration of CCL2 is low CXCL8 helps CXC-motif whereas the N-loop of CXCL8 is essential for CXCR1 to chemoattract monocytes. This requires binding of CXCL8 activation (Sarmiento et al., 2011). Furthermore, the above men- to CXCR1 and CXCR2. A further example is the synergism tioned CXCL8 variant displays anti-inflammatory properties since of CXCL12 with CCL2 where correct binding and signaling to it activates CXCR1 by desensitization of the CXCR2 response CXCR4 and CCR2 is essential for synergistic interactions. Addi- in human neutrophils. In fact, this agonist could help to clarify tionally a recent study has shown that CCR1-agonists like CCL5 the biological and physiological function, especially of CXCR1, in and CCL3 are enhancing CXCR4-induced ERK phosphoryla- inflammatory diseases. Thus R6H-CXCL8 is a potential candidate tion and chemotaxis of mononuclear cells and it was further as a therapeutic molecule. observed that this cooperative effect is inhibited by blocking CCR1 with specific antibodies and AMD3100 (Gouwy et al., GLYCOSAMINOGLYCAN BINDING AFFINITY 2011). Most chemokines have the ability to bind GAGs located on In summary, synergism of chemokines crucially depends on the cell surface. The enhancement or reduction of this prop- increased activation of the GPCR by heteromerization of lig- erty can diminish the GPCR signaling by an indirect blockade and and non-ligand chemokines or cooperative interactions after of chemokine binding to its receptor, since GAGs are co-factors chemokine activation of distinct GPCRs. Heteromerization of for GPCR activation. It is assumed that chemokines first bind the receptors has been observed. However the mechanistic role of these GAG co-receptor followed by GPCR activation. complexes in respect of ligand binding is still unclear, it might be A variety of chemokines was previously designed with altered that chemokine heteromers can stabilize and change the functional GAG-binding affinities resulting in a loss of GPCR activation activity of receptor heteromers (Thelen et al., 2010; Kramp et al., (Proudfoot et al., 2008; Shahrara et al., 2008; Rek et al., 2009). 2011). The activity of the pro-inflammatory chemokine CCL5 depends

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on the binding to GAGs. The substitution of positively charged binding site (Bertini et al., 2012). Some CXCR2- and CCR2- residues into alanine in the 40s loop ([44AANA47]-CCL5mutant) specific antagonists (i.e., reparixin and MLN1202) have already results in defective heparin binding and loss of the ability to recruit been tested as therapeutic drugs in clinical trials, like MLN1202, monocytes. The heteromerization of both CCL5 variants leads to which is a CCR2-blocking monoclonal antibody shown to reduce non-functional heteromers with a lack of GAG-binding efficiency high-sensitivity CRP as surrogate parameter for atherosclerosis (Johnson et al., 2004; Koenen and Weber, 2010b). Another study (Allegretti et al., 2008; Gilbert et al., 2011). (Braunersreuther et al.,2008) additionally confirms [44AANA47]- CCL5 as a potential therapeutic agent against atherosclerosis. But CHEMOKINE HETEROMERIZATION in contrast to Met-RANTES, [44AANA47]-CCL5 does not directly As mentioned before some chemokines inherently exhibit syner- abolish GPCR activation. Thus variations of CCL5 mutants act- gistic function toward other chemokines which mostly depends ing in different ways can lead to anti-inflammatory properties by on heteromerization. Disruption or changing these critical het- a direct blockade of the GPCR or by indirect inhibition through erophilic interactions might entail a decrease in the physiological prevention of chemokine binding to GAGs on the cell surface. response which has an impact on the degree of inflammation. A Another way to block chemokine activity using the affinity for prominent example is the heterophilic interaction between CXCL4 GAGs is to design dominant-negative mutants with a higher GAG- and CCL5 which results in a synergistic enhancement of CCL5 binding affinity compared to the wild type chemokine (Brandner induced signaling accompanied by increased monocyte recruit- et al., 2009). H23K-RANTES showed attenuation of autoimmune ment to the inflamed endothelium (Koenen et al., 2009; Koenen uveitis in rats based on displacement of wild type CCL5 from its and Weber, 2010a). Interruption of the chemokine heteromeriza- proteoglycan-co-receptor. Mutants with increased GAG-binding tion by cyclic peptides was shown to eliminate synergistic effect potential were designed for CCL2, as well. The PA508 mutant in vitro and in vivo. Recently it was shown (Grommes et al., of CCL2 exhibits no ability for CCR2 activation but a fourfold 2012)that small peptide antagonists, disrupting CXCL4–CCL5 higher GAG affinity compared to the wild type CCL2 (Piccinini heteromer formation in mouse models of acute lung injury, result et al., 2010). In a recent study in mice, PA508-CCL2 showed pre- in improved lung edema, less neutrophil infiltration, and reduced vention of neointima formation and reduction of tissue damage tissue damage. Thus targeting heterophilic chemokine interac- after myocardial infarction without notable side effects. Therefore, tions can act as therapeutic approach by attenuating inflammatory it could be a candidate as a therapeutic agent in reducing restenosis disease in a mild way. in stents (Liehn et al., 2010). Additionally, a mutant of CXCL12 with a deficiency in heparan sulfate binding can still transduce sig- CONCLUSION nals through CXCR4 but is not able to promote transendothelial It is still elusive which consequences the blockade of one migration in vitro. In vivo experiments could further show that chemokine has when entering clinical trials. For example, the den- this mutant efficiently down-regulates the CXCR4 expression and dritic cell-derived CCL17 could be identified as a catalyzer for desensitizes the chemotactic response toward CXCL12. Hence, this atherosclerosis due to interference of Treg homeostasis in mice modified chemokine might work in anti-inflammatory therapies (Weber et al., 2011). Blocking CCL17 with an antibody abolished (O’Boyle et al., 2009). this pro-inflammatory effect. Nevertheless the blocking mecha- nism is unclear and which consequences the blocking has for SMALL MOLECULES AND ANTIBODIES other physiological signal cascades. For example the CXCL12– The development of small molecules blocking GPCR activation CXCR4 axis is crucial for the CXCL12-dependent recruitment of is a powerful tool for the treatment of inflammatory diseases. progenitor cells. Consequently a reduction of the CXCR4 level Major efforts have been done to find drugs for blocking HIV infec- diminishes this important process in regeneration but inversely a tion. (Celsentri/Selzentry; Pfizer) was established as a decreased expression of CXCR4 was efficient to limit myocardial functional anti-HIV drug by blocking CCR5 as important entry infarct size in mice (Liehn et al., 2011). Detailed knowledge and receptor. In inflammatory diseases, like atherosclerosis, TAK779 clarity of how a specific chemokine oligomerizes, binds to GAG and nbI-74330 antagonists for CCR5 and CXCR9, respectively, and its GPCR as well as its interaction with other chemokines, with represent suitable therapeutic agents (Koenen and Weber, 2010b). regard of the resulting signal cascade and immune response, are Antagonizing CXCR4 by TAK779 additionally blocks leukocyte required. trafficking induced by CXCL12 (Sohy et al., 2009). Recently, Targeting GAG-binding sites of specific chemokines is a DF 2156A was introduced as a novel dual inhibitor of CXCL8 promising approach for developing drugs against chemokine dri- receptors CXCR1 and CXCR2 (Bertini et al., 2012). This dual ven diseases, given that the GPCR binding is not directly affected. function is based on a non-competitive inhibition resulting in Also the disruption of chemokine–chemokine interactions seems a stabilized binding between DF 2156A and the two CXCL8 recep- to become attractive, since synergistic effects can be prevented tors due to formation of specific ionic bonds in the allosteric without reducing the function of the respective chemokine per se.

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