Syk-Dependent Cytokine Induction by Dectin-1 Reveals a Novel Pattern Recognition Pathway for C Type Lectins

Abstract

Pattern-recognition receptors (PRRs) detect molecular signatures of microbes and initiate immune responses to infection. Prototypical PRRs such as Toll-like receptors (TLRs) signal via a conserved pathway to induce innate response genes. In contrast, the signaling pathways engaged by other classes of putative PRRs remain ill defined. Here, we demonstrate that the beta-glucan receptor Dectin-1, a yeast binding C type lectin known to synergize with TLR2 to induce TNF alpha and IL-12, can also promote synthesis of IL-2 and IL-10 through phosphorylation of the membrane proximal tyrosine in the cytoplasmic domain and recruitment of Syk kinase. syk-/- dendritic cells (DCs) do not make IL-10 or IL-2 upon yeast stimulation but produce IL-12, indicating that the Dectin-1/Syk and Dectin-1/TLR2 pathways can operate independently. These results identify a novel signaling pathway involved in pattern recognition by C type lectins and suggest a potential role for Syk kinase in regulation of innate immunity.

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

“…Thus, one would predict that lack of Syk and/or BTK in DC affects Dectin-1-mediated inflammatory cytokine production, as PLCg2-deficiency does. Accordingly, a previous study showed that lack of Syk impairs Dectin-1 function [8,9,18]. To further extend this study, we asked whether BTK is required for cytokine responses to b-glucan.…”

“…Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.…”

“…Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14].…”

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…Signaling through an immunoreceptor tyrosinebased activation motif (ITAM)-like motif allows dectin-1 to generate inflammatory responses in addition to its role as a phagocytosis receptor. Ligand binding results in phosphorylation of the ITAM motif, leading to the activation of the downstream tyrosine kinase Syk, CARD9 and initiation of phagocytosis, respiratory burst and production of the cytokines IL-2 and 26].…”

“…Signaling through an immunoreceptor tyrosinebased activation motif (ITAM)-like motif allows dectin-1 to generate inflammatory responses in addition to its role as a phagocytosis receptor. Ligand binding results in phosphorylation of the ITAM motif, leading to the activation of the downstream tyrosine kinase Syk, CARD9 and initiation of phagocytosis, respiratory burst and production of the cytokines IL-2 and 26].In addition to dectin-1 and TLR2, complement receptors such as CR3 have also been shown to bind directly to non-opsonized zymosan via their lectin domains [27,28]. In addition, SIGNR1 [29] and the mannose-receptor (MR) can also bind fungal components, but these receptors are mainly expressed by macrophages [11,30,31].…”