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bioRxiv · 10.64898/2026.09.24.754070

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

Jiang, Z.·Bo, L.·Li, N.·Chen, H.·Li, T.·Zhang, Y.·Deng, X.-m.·Bian, J.
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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.

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Jiang, Z., Bo, L., Li, N., Chen, H., Li, T., Zhang, Y., Deng, X.-m., Bian, J.. 2026-09-29. Inflammation-induced of Clec18a inhibits immune responses via Trpm7-dependent Cbl activation. https://doi.org/10.64898/2026.09.24.754070

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