Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors This information is current as Jenny Ostrop and Roland Lang of September 27, 2021. J Immunol 2017; 198:1403-1414; ; doi: 10.4049/jimmunol.1601665 http://www.jimmunol.org/content/198/4/1403 Downloaded from References This article cites 202 articles, 75 of which you can access for free at: http://www.jimmunol.org/content/198/4/1403.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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Th eJournal of Brief Reviews Immunology Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors Jenny Ostrop*,† and Roland Lang‡ Several spleen tyrosine kinase–coupled C-type lectin of TLRs and crosstalk of TLR signaling have been studied for receptors (CLRs) have emerged as important pattern almost two decades. C-type lectin receptors (CLRs) as another recognition receptors for infectious danger. Because major group of PRRs have entered the field later, but their encounter with microbial pathogens leads to the simul- investigation has gained much momentum in the last decade. taneous ligation of several CLRs and TLRs, the signals Many studies have been conducted on CLRs assigned to the so- emanating from different pattern recognition receptors called dendritic cell (DC)–associated C-type lectin (Dectin)-1 have to be integrated to achieve appropriate biological or Dectin-2 clusters, localized within the NK cell gene cluster responses. In this review, we briefly summarize current on human chromosome 12 or mouse chromosome 6 (1–3). Downloaded from knowledge about ligand recognition and core signaling Several excellent reviews on the function of these CLRs in by Syk-coupled CLRs. We then address mechanisms of antimicrobial defense and homeostasis are available (4, 5). In synergistic and antagonistic crosstalk between different this review we summarize the current knowledge about sig- CLRs and with TLRs. Emerging evidence suggests that naling downstream of the activating CLR Dectin-1 (Clec7a), signal integration occurs through 1) direct interaction Dectin-2 (human Clec6a, mouse Clec4n), macrophage-inducible http://www.jimmunol.org/ between receptors, 2) regulation of expression levels C-type lectin (Mincle; Clec4e), and macrophage C-type lectin and localization, and 3) collaborative or conflicting sig- (Mcl; Clec4d) that is largely dependent on the kinase spleen naling interference. Accordingly, we aim to provide a tyrosine kinase (Syk). Table I provides an overview of defined ligands and microorganisms bound by this group of PRRs. In conceptual framework for the complex and sometimes addition to microbial carbohydrate and glycolipid structures unexpected outcome of CLR ligation in bacterial and acting as PAMPs, several CLRs bind endogenous ligands such as fungal infection. The Journal of Immunology, 2017, SAP130 released by dying cells or cholesterol crystals. Thus, these 198: 1403–1414. CLRs are involved in homeostatic responses and inflammatory conditions (6–9), in addition to host response to pathogens and by guest on September 27, 2021 he immune system identifies invading microbial patho- commensals (10–12). CLR-induced APC activation directs Th gens by conserved microbial motifs, known as pathogen- cell differentiation [see Geijtenbeek and Gringhuis (13) for T associated molecular patterns (PAMPs). For any given review], and synthetic ligands for CLRs are under development pathogen a combination of such PAMPs is recognized by pattern as adjuvants (14, 15). Bacteria and fungi can express more recognition receptors (PRRs) on innate immune cells. Detection than one CLR ligand, and therefore simultaneous engage- of a pathogen by a combination of receptors ensures redundancy ment of CLRs during recognition of microbial pathogens is and results in lower likelihood for immune evasion by the likely. Additionally, concurrent activation of TLRs and pathogen and robustness against genetic diversity in the host. CLRs will occur, leading to synergistic and antagonistic re- Furthermore, engagement of a pathogen-specific set of receptors sponses with sometimes unexpected outcomes. For a gen- allows tailoring of the immune response to protect the body eralized concept of signal integration in innate immunity, we against specific infections. refer to a recent publication by Elinav and colleagues (16). TLRs are the best studied family of PRRs expressed on With regard to CLR signaling, there is evidence that Dectin-1, innate immune cells. Ten functional TLRs are known in Dectin-2, Mincle, and Mcl not only act as activating PRRs, but humans, and twelve have been described in mice. Interactions they are particularly important for regulation and tailoring of *Center of Molecular Inflammation Research, Norwegian University of Science and or Center of Molecular Inflammation Research and Department of Cancer Research Technology, 7491 Trondheim, Norway; †Department of Cancer Research and Molec- and Molecular Medicine, Norwegian University of Science and Technology, 7491 ular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Trondheim, Norway (J.O.). E-mail addresses: [email protected] (R.L.) or Norway; and ‡Mikrobiologisches Institut–Klinische Mikrobiologie, Immunologie und [email protected] (J.O.) Hygiene, Universita¨tsklinikum Erlangen, Friedrich-Alexander-Universita¨t Erlangen– Abbreviations used in this article: CLR, C-type lectin receptor; CR3, complement Nurnberg,€ 91054 Erlangen, Germany receptor 3; CTLD, C-type lectin domain; DC, dendritic cell; Dectin, dendritic cell– ORCID: 0000-0003-0502-3677 (R.L.). associated C-type lectin; IRAK, IL-1R–associated kinase; IRF, IFN regulatory factor; iNOS, inducible NO synthase; Mcl, macrophage C-type lectin; Mincle, macrophage- Received for publication September 30, 2016. Accepted for publication November 14, inducible C-type lectin; PAMP, pathogen-associated molecular pattern; PKC, protein 2016. kinase C; PLC, phospholipase C; PRR, pattern recognition receptor; ROS, reactive This work was supported by Research Council of Norway Centers of Excellence Grant oxygen species; SOCS, suppressor of cytokine signaling; Syk, spleen tyrosine kinase; 223255/F50 (to J.O.) and German Research Foundation Grants RTG1660, TP-A2 and TDB, trehalose dibehenate; TDM, trehalose dimycolate; TIR, Toll/IL-1R; TRIF, CRC796, TP-B6 (to R.L.). Toll/IL-1R domain–containing adapter inducing IFN-b. Address correspondence and reprint requests to Prof. Roland Lang or Dr. Jenny Ostrop, Ó Universita¨tsklinikum Erlangen, Wasserturmstrasse 3-5, 91054 Erlangen, Germany (R.L.) Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601665 1404 BRIEF REVIEWS: SIGNALING CROSS-TALK OF Syk-COUPLED CLRs immune responses. In this review, we discuss the interactions Syk-coupled CLRs: Structure, ligands, and signaling following simultaneous engagement of several CLRs and We concentrate in the following on reviewing the current TLRs. Conceptually, we propose that such signal integration literature on Dectin-1 and the Dectin-2, Mcl and Mincle. can occur on different levels, which are discussed in this Dectin-1 and the Dectin-1 subfamily. Dectin-1 is the best studied structured review: 1) contact between receptors, with pos- receptor in the Dectin-1 family; signaling events downstream sible consequences for ligand binding, receptor stability, or of Dectin-1 ligation are often regarded as prototypic for Syk- localization; 2) control of receptor expression levels, adjusting coupled CLRs (28, 29). Dectin-1 recognizes b-glucans in the responsiveness; 3) collaborative signaling, leading to syn- fungal and mycobacterial cell walls in a Ca2+-independent ergistic responses; and 4) conflicting signaling, tailoring the manner (30–33) (see Table I). b-Glucans bind to Dectin-1 inflammatory response. homodimers, and ligand binding has been suggested to induce oligomerization (34). Whereas particulate ligands CLRs and TLRs activate distinct inflammatory pathways and gene result in formation of a “phagocytic synapse,” stimulation expression programs with a soluble ligand does not induce a response (35). Ligand binding to either the extracellular or endosomal Dectin-1 signals via its internal hemITAM motif (single ectodomain of TLRs leads to dimerization of the cytoplasmic YxxL/I motif) (36), which is phosphorylated upon ligand Toll/IL-1R (TIR) domain. Dimerization can occur as both binding. Recruitment of Syk to the phosphorylated hemITAM is pivotal for Dectin-1 responses (37) and requires a phosphatase- homo- or heterodimers (TLR1/TLR2 and TLR2/TLR6). Downloaded from Adaptor proteins are subsequently