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

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 Hambardzumyan; Tom Hamilton; Richard M Ransohoff; Xiaoxia Li

doi:10.1038/ncomms15508

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

Journal article

Open access

Peer reviewed

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

Chenhui Wang, Cun-Jin Zhang, Bradley N Martin, Katarzyna Bulek, Zizhen Kang, Junjie Zhao, Guanglin Bian, Julie A Carman, Ji Gao, Ashok Dongre, …

Nature communications, Vol.8(1), pp.15508-15508

05/31/2017

DOI: 10.1038/ncomms15508

PMCID: PMC5460031

PMID: 28561022

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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.

Animals

Astrocytes

Cell Differentiation - immunology

Cell Proliferation - physiology

Coculture Techniques

Encephalomyelitis, Autoimmune, Experimental - immunology

Female

HEK293 Cells

HeLa Cells

Humans

Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics

Immunoglobulin J Recombination Signal Sequence-Binding Protein - immunology

Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism

Interleukin-17 - immunology

Interleukin-17 - metabolism

Mice

Mice, Inbred C57BL

Mice, Transgenic

Multiple Sclerosis - immunology

Oligodendrocyte Precursor Cells - physiology

Primary Cell Culture

Protein Binding - immunology

Protein Domains - physiology

Receptor, Notch1 - genetics

Receptor, Notch1 - immunology

Receptor, Notch1 - metabolism

Receptors, Interleukin-17 - metabolism

Remyelination - physiology

Signal Transduction - immunology

Th1 Cells - immunology

Th17 Cells - immunology

Th17 Cells - metabolism

Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - metabolism

Details

Title: Subtitle: IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression
Creators: Chenhui Wang - Cleveland Clinic
Cun-Jin Zhang - Tianjin Medical University
Bradley N Martin - Case Western Reserve University
Katarzyna Bulek - Cleveland Clinic
Zizhen Kang - Shanghai Jiao Tong University
Junjie Zhao - Cleveland Clinic
Guanglin Bian - Cleveland Clinic
Julie A Carman - Bristol-Myers Squibb
Ji Gao - Bristol-Myers Squibb
Ashok Dongre - Bristol-Myers Squibb
Haibo Xue - Binzhou University
Stephen D Miller - Northwestern University
Youcun Qian - Shanghai Jiao Tong University
Dolores Hambardzumyan - Emory University
Tom Hamilton - Cleveland Clinic
Richard M Ransohoff - IDEC
Xiaoxia Li - Cleveland Clinic
Resource Type: Journal article
Publication Details: Nature communications, Vol.8(1), pp.15508-15508
DOI: 10.1038/ncomms15508
PMID: 28561022
PMCID: PMC5460031
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: P01 CA062220 / NCI NIH HHS P01 HL103453 / NHLBI NIH HHS P01 HL029582 / NHLBI NIH HHS R01 NS071996 / NINDS NIH HHS U10 HL109250 / NHLBI NIH HHS
Language: English
Date published: 05/31/2017
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984201255902771

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