Signaling by myeloid C-type lectin receptors in immunity and homeostasis

Abstract

Myeloid cells are key drivers of physiological responses to pathogen invasion or tissue damage. Members of the C-type lectin receptor (CLR) family stand out among the specialized receptors utilized by myeloid cells to orchestrate these responses. CLR ligands include carbohydrate, protein, and lipid components of both pathogens and self, which variably trigger endocytic, phagocytic, proinflammatory, or anti-inflammatory reactions. These varied outcomes rely on a versatile system for CLR signaling that includes tyrosine-based motifs that recruit kinases, phosphatases, or endocytic adaptors as well as nontyrosine-based signals that modulate the activation of other pathways or couple to the uptake machinery. Here, we review the signaling properties of myeloid CLRs and how they impact the role of myeloid cells in innate and adaptive immunity.

Figure 1. Signaling families of myeloid CLRs

Myeloid CLRs can be grouped independently of structure into four groups, based on cytoplasmic signaling motifs and the binding of early adaptors, kinases or phosphatases,: a) hemITAM-coupled CLRs signal via Syk through a single tyrosine-based motif in their tail. b) ITAM-coupled CLRs signal via Syk through association with ITAM-bearing adaptors as FcRγ chain or DAP-12. c) ITIM-containing CLRs possess an ITIM motif that can recruit phosphatases SHP-1 and SHP-2. d) ITAM-ITIM-independent CLRs do not signal through Syk or phosphatases although they may contain tyrosine-based motifs involved in endocytosis.

Figure 2. Dectin-1 as a model hemITAM-coupled receptor

Following binding to agonist ligands, Dectin-1 recruits Syk through a phospho-tyrosine in the hemITAM motif. Syk induces production of ROS that acts as microbicidal agent and contributes to the activation of the NALP3 inflammasome, leading to processing of pro-IL-1β. Syk also leads to activation of NF-κB at different levels. First, Syk recruits CARD9/Bcl-10 to activate the canonical p65/p50 pathway and Malt-1, which activates c-Rel in human DC. Independent of CARD9, Syk also leads to activation of NIK and the non-canonical RelB pathway. Finally, Dectin-1 engagement also leads to Syk-independent activation of Raf-1, which results in acetylation of p65/p50 and modulation of NF-κB activity in part through inhibition of the RelB module. Syk also activates the p38, ERK and JNK cascades, as well as NFAT, which regulate gene transcription in cooperation with NF-κB.

Figure 3. Dectin-2 as a model ITAM-coupled receptor

Dectin-2 associates with the FcRγ chain via an arginine residue located in the transmembrane region. Upon Dectin-2 triggering, Syk is recruited to the phosphorylated ITAM of FcRγ and coordinates activation of many of the same pathways as for Dectin-1 signaling (see legend to Fig. 2 and text for discussion of differences between Dectin-1 and Dectin-2). Dectin-2 / Syk signaling in response to allergens can also lead to synthesis of cysteinyl leukotrienes, which are involved in allergic inflammation and induction of Th2 responses.

Figure 4. DCIR and Dcir1 as model ITIM-containing CLRs

The phosphorylation of the tyrosine in the ITIM domain allows binding of SHP1 and SHP-2 phosphatases. Human DCIR inhibits signaling to NF-κB and modulates the pattern of genes activated by TLR although it is unclear whether this is a direct effect. Dcir1 also inhibits ITAM signaling by unidentified receptors and impairs recruitment and activation of Stat5 by the GM-CSF receptor, limiting DC expansion.

Figure 5. DC-SIGN as a model ITAM-ITIM-independent receptor

Binding of different ligands results in recruitment of different effectors to the tail of DC-SIGN. High mannose ligands such as ManLAM promote binding of LSP1, KSR1 and CNK in a tyrosine-independent fashion. This complex triggers the small GTPase Ras, which activates Raf-1. Raf-1 activation culminates in acetylation of NF-κB p65 and alters the pattern of gene expression induced through TLR signaling. Fucose-based ligands promote binding of LSP1 only, which acts in a Raf-1-independent fashion to enhance TLR-dependent synthesis of IL-10 and to decrease production of pro-inflammatory cytokines. Finally, another DC-SIGN agonist, Salp15, activates a Raf-1/MEK pathway that promotes TNF and IL-6 mRNA decay and decreases production of IL-12 by impairing chromatin remodeling.