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IL-17 stimulation induces NOTCH1 activation in OPC, leading to Th17-mediated demyelinating disease

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2022-05-20

Multiple sclerosis is a disease of central nervous demyelination that is more common in Western countries and is increasing in number in China every year. The disease is usually characterized by a remitting, relapsing course, with a predilection for the optic nerve, spinal cord and brainstem. There is no good treatment for the disease, and the available drugs can only relieve and delay the disease process, but not cure it. Some patients with the disease eventually become paralyzed, which is very damaging to the quality of life. In particular, the disease mostly occurs in young and middle-aged people, causing a huge burden to families and society.

　　Recent studies have revealed that Th17 cells and their secreted IL-17 play an important role in the development of the disease. However, how IL-17 acts on central nervous cells and the mechanism of its action are still not well understood.

　　In May 17, researchers from Huazhong University of Science and Technology, Wuhan Institute of Biotechnology and Cleveland Clinic. Lerner Research Institute researchers found that IL-17 activates the NOTCH signaling pathway in oligodendrocyte precursor cells (OPCs) and can participate in cell proliferation as well as regulate cellular inflammatory cytokine expression. The crosstalks of IL-17 with NOTCH1, a pathway that promotes OPC proliferation and inhibits OPC differentiation leading to demyelinating disease, are reported.

　　IL-17, which has been discovered for 20 years, is a cytokine secreted by CD4+ T cells. IL-17 secreted by TH17 cells binds to target cells to promote inflammatory chemokines, acute phase proteins, and neutrophil aggregation, thereby playing a role in organismal immunity and autoimmune diseases.

　　This study found that IL-17 is able to act on oligodendrocyte precursor cells within the central nervous system and activate the NOTCH signaling pathway. IL-17-induced activation of the NOTCH signaling pathway is critical for disease development and acts primarily by affecting the expression of downstream signaling molecules.

　　Studies have shown that IL-17R interacts with NOTCH1 through the extracellular structural domain and promotes cleavage of the intracellular structural domain of NOTHC1 (NICD1). IL-17-induced activation of NOTCH1 leads to the interaction of the IL-17R bridging protein Act1 with NICD1, which then translocates the Act1-NICD1 complex into the nucleus. Act1-NICD1 is recruited to the promoters of several NOTCH1 target genes (including STEAP4, a metalloreductase important for inflammation and cell proliferation) that are specifically induced by Th17 cells in the spinal cord.

　　Further studies also showed that disruption of IL-17RA-NOTCH1 interaction by inhibitors would inhibit IL-17-induced NOTCH1 activation and attenuate Th17-mediated experimental autoimmune encephalitis (EAE).

　　Since the NOTCH signaling pathway has been more studied and some small molecule inhibitors have been used to inhibit the NOTCH pathway, this study suggests that these small molecule NOTCH inhibitors are likely to be used as therapeutic agents in multiple sclerosis.