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.

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells‐derived oligodendrocyte precursor cells

“…In particular, cytokine exposure during the proliferative phase leads to an increased proliferation and a differentiation block in both fetal and adult OPCs, as indicated by lineage progression marker analysis. Numerous in vitro and in vivo studies have indicated that inflammatory cytokines promote OPC proliferation, involving, among others, the VEGFR2 (Choi et al, 2018) and Notch pathways (Wang et al, 2017). Inflammatory cytokines are also proved to be involved specifically in the differentiation block of OPCs derived from the adult brain, affecting cell cycle exit and the expression of genes encoding for proteins that regulate and determine remyelination (Chew, King, Kennedy, & Gallo, 2005;Falahati et al, 2013;Kang et al, 2013;Su et al, 2011;Tanner, Cherry, & Mayer-Pröschel, 2011).…”

Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

“…IL‐17A, secreted by immune cells, plays a vital role in the stroke pathophysiology. In addition to its pro‐inflammatory effect, IL‐17A has been shown to promote hyperproliferation and differentiation of various cell types; the most notable are Th17 cells and γδT cells due to their production of IL‐17A . After hemorrhagic stroke, macrophages become activated and secret IL‐23, which promotes the activation of γδT cells and Th cells .…”

“…In addition to its pro-inflammatory effect, IL-17A has been shown to promote hyperproliferation and differentiation of various cell types; the most notable are Th17 cells and γδT cells due to their production of IL-17A. 17,[45][46][47][48] After hemorrhagic stroke, macrophages become activated and secret IL-23, which promotes the activation of γδT cells and Th cells. 18 Due to the blood-brain barrier (BBB) rupture after hemorrhagic stroke, 49 IL-17A enters into the brain tissue through the serum.…”

Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming

“…Moreover, Notch1 receptor has been shown to modulate T cell chemotaxis to the CNS, T cell IFN-γ and IL-17 expression in Th1 and Th17 cells, and Treg functions [37]. Finally, a role for Notch1 in the IL-17 promotion of oligodendrocyte proliferation and inhibition of differentiation has also been described in relation to EAE progression [44].…”