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

• DOI: 10.1038/ncomms15508
• Publication Date: 2017-05-31T12:10:46Z
• Authors: 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; Dolores Hambardzu...; Tom Hamilton; Richard M. Ransohoff; Xiaoxia Li
• Keywords: 0301 basic medicine; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Science; Primary Cell Culture; Mice, Transgenic; Article; Mice; 03 medical and health sciences; Animals; Humans; Adaptor Proteins, Signal Transducing; Cell Proliferation; Oligodendrocyte Precursor Cells; Q; Interleukin-17; Cell Differentiation; Coculture Techniques; Mice, Inbred C57BL; HEK293 Cells; Astrocytes; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Female; HeLa Cells; Protein Binding

AbstractNOTCH1 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.