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IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression

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  • Chenhui Wang

    (Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology
    Lerner Research Institute, Cleveland Clinic Foundation
    Wuhan Institute of Biotechnology)

  • Cun-Jin Zhang

    (Lerner Research Institute, Cleveland Clinic Foundation
    Tianjin Neurological Institute, Tianjin Medical University General Hospital)

  • Bradley N. Martin

    (Lerner Research Institute, Cleveland Clinic Foundation
    Case Western Reserve University, School of Medicine)

  • Katarzyna Bulek

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Zizhen Kang

    (Lerner Research Institute, Cleveland Clinic Foundation
    Shanghai Institute of Immunology, Shanghai Jiaotong University of School of Medicine)

  • Junjie Zhao

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Guanglin Bian

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Julie A. Carman

    (Discovery Biology, Bristol-Myers Squibb)

  • Ji Gao

    (Discovery Biology, Bristol-Myers Squibb)

  • Ashok Dongre

    (Discovery Biology, Bristol-Myers Squibb)

  • Haibo Xue

    (Binzhou Medical University Hospital)

  • Stephen D. Miller

    (Feinberg School of Medicine, Northwestern University)

  • Youcun Qian

    (The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine
    Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine)

  • Dolores Hambardzumyan

    (Aflac Cancer and Blood Disorders Center, Emory University)

  • Tom Hamilton

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Richard M. Ransohoff

    (Biogen Idec)

  • Xiaoxia Li

    (Lerner Research Institute, Cleveland Clinic Foundation)

Abstract

NOTCH1 signalling contributes to defective remyelination by impairing differentiation of oligodendrocyte progenitor cells (OPCs). Here we report that IL-17 stimulation induces NOTCH1 activation in OPCs, contributing to Th17-mediated demyelinating disease. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NOTHC1 intracellular domain (NICD1). IL-17-induced NOTCH1 activation results in the interaction of IL-17R adaptor Act1 with NICD1, followed by the translocation of the Act1–NICD1 complex into the nucleus. Act1–NICD1 are recruited to the promoters of several NOTCH1 target genes (including STEAP4, a metalloreductase important for inflammation and cell proliferation) that are specifically induced in the spinal cord by Th17 cells. A decoy peptide disrupting the IL-17RA–NOTCH1 interaction inhibits IL-17-induced NOTCH1 activation and attenuates Th17-mediated experimental autoimmune encephalitis (EAE). Taken together, these findings demonstrate critical crosstalk between the IL-17 and NOTCH1 pathway, regulating Th17-induced inflammatory and proliferative genes to promote demyelinating disease.

Suggested Citation

  • Chenhui Wang & Cun-Jin Zhang & Bradley N. Martin & Katarzyna Bulek & Zizhen Kang & Junjie Zhao & Guanglin Bian & Julie A. Carman & Ji Gao & Ashok Dongre & Haibo Xue & Stephen D. Miller & Youcun Qian &, 2017. "IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15508
    DOI: 10.1038/ncomms15508
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