TH17 cells promote CNS inflammation by sensing danger signals via Mincle
Quanri Zhang1, Weiwei Liu1, Han Wang1
1Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
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.
Insights
Mincle receptor on T cells drives autoimmune brain inflammation. This immune sensor recognizes danger signals, promoting TH17 cell expansion and experimental autoimmune encephalomyelitis (EAE) progression.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- C-type lectin receptor Mincle recognizes damage-associated molecular patterns.
- Mincle's role in T cells, particularly in autoimmune diseases, is not well understood.
Purpose of the Study:
- To investigate the T cell-intrinsic role of Mincle in experimental autoimmune encephalomyelitis (EAE).
- To elucidate the molecular mechanisms by which Mincle influences TH17 cell responses in CNS inflammation.
Main Methods:
- Utilized Mincle-deficient T cells in a mouse model of EAE.
- Analyzed Mincle expression in TH17 and TH1 cells.
- Investigated the role of beta-glucosylceramide as a Mincle ligand.
- Assessed inflammasome activation (ASC-NLRP3, Caspase8) and IL-1beta production.
- Evaluated the impact of inhibiting beta-glucosylceramide synthesis on EAE.
Main Results:
- Genomic deletion of Mincle in T cells significantly impaired EAE.
- Mincle expression was higher in TH17 cells than TH1 cells.
- Dying cells released beta-glucosylceramide, a natural Mincle ligand.
- Mincle activation led to ASC-NLRP3 inflammasome activation, Caspase8-dependent IL-1beta production, and TH17 cell proliferation.
- Inhibiting beta-glucosylceramide synthesis reduced CNS inflammatory CD4+ T cells and EAE progression.
Conclusions:
- Mincle has a critical T cell-intrinsic role in promoting CNS inflammation during EAE.
- Mincle on TH17 cells senses danger signals, driving autoimmune pathogenesis.
- Targeting Mincle or its ligand pathway may offer therapeutic strategies for neuroinflammatory diseases.
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