Inflammation-mediated induction of Clec18a inhibits immune responses via Trpm7-dependent Cbl activation

Abstract

Innate immune responses must be tightly controlled to maintain immuno-homeostasis. However, the regulatory mechanisms underlying the activation and early stages of the innate immune response remain poorly defined. Here, we found the soluble C-type lectin Clec18a is up-regulated in multiple inflammatory diseases, including sepsis and influenza, and secreted within minutes upon activation in multiple immune cells, including macrophages, dendritic cells (DCs), and T cells. Clec18a-myeloid-knockout mice exhibited reduced survival and exacerbated inflammation than the wild-type. However, exogenous recombinant Clec18a administration alleviated inflammation both in vitro and in vivo. Mechanistically, we identified macrophage-inducible C-type lectin (Mincle) as the receptor of Clec18a. Clec18a-Mincle binding triggers Trpm7-dependent calcium influx, which activates the ubiquitin E3 ligase Cbl and leads to Mincle-Cbl-MyD88-Trpm7 complex formation and degradation. Cbl deficiency, calcium inhibition and Trpm7 knockdown abrogated Clec18a-mediated immune suppression. Thus, our study revealed Clec18a as a critical checkpoint on the initiation of innate immune response through an intrinsic crosstalk between CLR and TLR signaling. Graphical abstract Inflammation-induced Clec18a secretion binds to Mincle, triggering Trpm7-mediated extracellular calcium influx, directly activates Cbl and orchestrates the assembly of the Mincle-Trpm7-Cbl-MyD88 complex. Subsequent ubiquitination leads to proteasomal degradation of this complex, thereby abrogating CLR-TLR signaling crosstalk.