TH17 cells promote CNS inflammation by sensing danger signals via Mincle
Quanri Zhang, Weiwei Liu, Han Wang, Hao Zhou, Katarzyna Bulek, Xing Chen, Cun‐Jin Zhang, Junjie Zhao, Renliang Zhang, Caini Liu, Zizhen Kang, Robert A Bermel, George Dubyak, Derek W. Abbott, Tsan Sam Xiao, Laura E. Nagy, Xiaoxia Li
Abstract
The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell-intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release β-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1β production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of β-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.