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

Nat Commun. 2017 May 31:8:15508. doi: 10.1038/ncomms15508.

Authors

Chenhui Wang^{1

2

3}, Cun-Jin Zhang^{2

4}, Bradley N Martin^{2

5}, Katarzyna Bulek², Zizhen Kang^{2

6}, Junjie Zhao², Guanglin Bian², Julie A Carman⁷, Ji Gao⁷, Ashok Dongre⁷, Haibo Xue⁸, Stephen D Miller⁹, Youcun Qian^{10

11}, Dolores Hambardzumyan¹², Tom Hamilton², Richard M Ransohoff¹³, Xiaoxia Li²

Affiliations

¹ Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
² Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
³ Wuhan Institute of Biotechnology, Wuhan 430075, China.
⁴ Department of Neurology and Immunology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
⁵ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA.
⁶ Shanghai Institute of Immunology, Shanghai Jiaotong University of School of Medicine, 280 South Chongqing Rd, Huangpu, Shanghai 200025, China.
⁷ Discovery Biology, Bristol-Myers Squibb, Princeton, New Jersey 08540, USA.
⁸ The Department of Endocrinology and Metabolism, Binzhou Medical University Hospital. Binzhou City, Shandong Province 256603, China.
⁹ Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
¹⁰ 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 200031, China.
¹¹ Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China.
¹² Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University. 201 Dowman Drive. Atlanta, Georgia 30322 USA.
¹³ Biogen Idec, Cambridge, Massachusetts 02142, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
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

Substances

Adaptor Proteins, Signal Transducing
IL17RA protein, human
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Interleukin-17
NOTCH1 protein, human
RBPJ protein, human
Receptor, Notch1
Receptors, Interleukin-17
TRAF3IP2 protein, human
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding