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

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

^*Corresponding author for this work

Microbiology-Immunology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

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.

Original language	English (US)
Article number	15508
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15508
State	Published - May 31 2017

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Wang, C., Zhang, C. J., Martin, B. N., Bulek, K., Kang, Z., Zhao, J., Bian, G., Carman, J. A., Gao, J., Dongre, A., Xue, H., Miller, S. D., Qian, Y., Hambardzumyan, D., Hamilton, T., Ransohoff, R. M., & Li, X. (2017). IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nature communications, 8, Article 15508. https://doi.org/10.1038/ncomms15508

@article{08ad4292728a4010af8197b79a71dd8b,

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

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.",

author = "Chenhui Wang and Zhang, {Cun Jin} and Martin, {Bradley N.} and Katarzyna Bulek and Zizhen Kang and Junjie Zhao and Guanglin Bian and Carman, {Julie A.} and Ji Gao and Ashok Dongre and Haibo Xue and Miller, {Stephen D.} and Youcun Qian and Dolores Hambardzumyan and Tom Hamilton and Ransohoff, {Richard M.} and Xiaoxia Li",

note = "Funding Information: National Natural Science Foundation of China (NO. 31329002 to Y.Q.)",

year = "2017",

month = may,

day = "31",

doi = "10.1038/ncomms15508",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Wang, C, Zhang, CJ, Martin, BN, Bulek, K, Kang, Z, Zhao, J, Bian, G, Carman, JA, Gao, J, Dongre, A, Xue, H, Miller, SD, Qian, Y, Hambardzumyan, D, Hamilton, T, Ransohoff, RM & Li, X 2017, 'IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression', Nature communications, vol. 8, 15508. https://doi.org/10.1038/ncomms15508

TY - JOUR

T1 - IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression

AU - Wang, Chenhui

AU - Zhang, Cun Jin

AU - Martin, Bradley N.

AU - Bulek, Katarzyna

AU - Kang, Zizhen

AU - Zhao, Junjie

AU - Bian, Guanglin

AU - Carman, Julie A.

AU - Gao, Ji

AU - Dongre, Ashok

AU - Xue, Haibo

AU - Miller, Stephen D.

AU - Qian, Youcun

AU - Hambardzumyan, Dolores

AU - Hamilton, Tom

AU - Ransohoff, Richard M.

AU - Li, Xiaoxia

N1 - Funding Information: National Natural Science Foundation of China (NO. 31329002 to Y.Q.)

PY - 2017/5/31

Y1 - 2017/5/31

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms15508

DO - 10.1038/ncomms15508

M3 - Article

C2 - 28561022

AN - SCOPUS:85019997543

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 15508

ER -

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

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