Mechanism of C-type lectin receptor Dectin-1 and DC-ASGPR-mediated immune modulation.
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Gu, Chao, 1987-
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Dendritic cells (DCs) are major antigen-presenting cells (APCs) and play a critical role in directing host immune responses towards either immunity or tolerance. C-type lectin receptors (CLRs) expressed on DCs not only facilitate antigen capture and uptake for presentation, but also deliver diverse intracellular signals that modulate DC functions and result in altered immune responses. Among numerous CLRs, Dectin-1 is critical to induce both Th1 and Th17 cell responses that are essential to host immune defense against fungi and mycobacteria whereas DC-ASGPR modulates immune responses by promoting antigen-specific regulatory T cells. Herein, we report that activation of CD11c+ myeloid DCs via Dectin-1 significantly downregulates TSLP-induced inflammatory Th2 cell responses by (1) subverting the Th2-permissive microenvironment via IL-10, (2) suppressing OX40L expression by downregulating the transcriptional activity of p50-RelB heterodimer and (3) decreasing Th2 cell-attracting chemokine CCL17 secretion. In addition, we dissected DC-ASGPR-mediated signaling pathway and found that DC-ASGPR ligation by specific monoclonal antibody (mAb) induces Syk activation. Similar to Dectin-1, engagement of PLCγ2 and PKCδ is conserved downstream of Syk activation upon DC-ASGPR triggering. Unexpectedly, however, DC-ASGPR ligation by mAb does not induce NF-κB activation. Instead, it selectively activates MAPK ERK1/2 and JNK. Rapid and prolonged phosphorylation of ERK1/2 leads to activation of p90RSK and CREB, promoting IL-10 expression in DCs. Moreover, DC-ASGPR ligation activates PI3K-Akt pathway, which differentially regulates the activities of GSK-3α/β and β-Catenin for cytokine expression. Our results provide a molecular explanation for the ability of DC-ASGPR-interacting ligands to preferentially evoke immune modulation. Data from this study support that both Dectin-1 and DC-ASGPR represent promising targets that may allow us to control host immune responses, particularly inflammatory responses.