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TH17 cells promote CNS inflammation by sensing danger signals via Mincle

Author

Listed:
  • Quanri Zhang

    (Cleveland Clinic, Lerner Research Institute)

  • Weiwei Liu

    (Cleveland Clinic, Lerner Research Institute)

  • Han Wang

    (Cleveland Clinic, Lerner Research Institute)

  • Hao Zhou

    (Cleveland Clinic, Lerner Research Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Katarzyna Bulek

    (Cleveland Clinic, Lerner Research Institute
    Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University)

  • Xing Chen

    (Cleveland Clinic, Lerner Research Institute)

  • Cun-Jin Zhang

    (Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University)

  • Junjie Zhao

    (Cleveland Clinic, Lerner Research Institute)

  • Renliang Zhang

    (Lerner Research Institute)

  • Caini Liu

    (Cleveland Clinic, Lerner Research Institute)

  • Zizhen Kang

    (University of Iowa)

  • Robert A. Bermel

    (Mellen Center for Multiple Sclerosis, Cleveland Clinic)

  • George Dubyak

    (University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine)

  • Derek W. Abbott

    (Case Western Reserve University)

  • Tsan Sam Xiao

    (Case Western Reserve University)

  • Laura E. Nagy

    (Cleveland Clinic, Lerner Research Institute
    Department of Gastroenterology and Hepatology, Cleveland Clinic
    Case Western Reserve University)

  • Xiaoxia Li

    (Cleveland Clinic, Lerner Research Institute)

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.

Suggested Citation

  • 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. Abb, 2022. "TH17 cells promote CNS inflammation by sensing danger signals via Mincle," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30174-1
    DOI: 10.1038/s41467-022-30174-1
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    References listed on IDEAS

    as
    1. Wook-Bin Lee & Ji-Seon Kang & Won Young Choi & Quanri Zhang & Chul Han Kim & Un Yung Choi & Jeongsil Kim-Ha & Young-Joon Kim, 2016. "Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    2. Paul R. Mangan & Laurie E. Harrington & Darrell B. O'Quinn & Whitney S. Helms & Daniel C. Bullard & Charles O. Elson & Robin D. Hatton & Sharon M. Wahl & Trenton R. Schoeb & Casey T. Weaver, 2006. "Transforming growth factor-β induces development of the TH17 lineage," Nature, Nature, vol. 441(7090), pages 231-234, May.
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