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Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells.

ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuronal demyelination. MS pathogenesis occurs via multiple mechanisms, and is mediated in part by oligodendrocyte apoptosis and a robust inflammatory response. In the present study, Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 kinase domain, was revealed to effectively alleviate the severity and pathological damage associated with experimental autoimmune encephalomyelitis (EAE), a commonly used mouse model of MS. In addition, treatment with Nec-1 significantly decreased the number of lesions and inflammatory cell infiltrates in spinal cord tissues, as well as the production of associated pro-inflammatory cytokines, including tumor necrosis factor ? (TNF?), interferon-? and interleukin-1?. Nec-1 also suppressed TNF? + zVAD-fmk-induced apoptosis and necroptosis in primary oligodendrocyte precursor cells. The present study revealed that Nec-1 effectively attenuated the progression of EAE by suppressing apoptosis and necroptosis in oligodendrocytes, and represents a potential novel therapeutic agent for the treatment of MS.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6781785 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells.

Wang Ying Y Guo Li L Wang Jueqiong J Shi Wei W Xia Zhilun Z Li Bin B

Experimental and therapeutic medicine 20190913 5

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuronal demyelination. MS pathogenesis occurs via multiple mechanisms, and is mediated in part by oligodendrocyte apoptosis and a robust inflammatory response. In the present study, Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 kinase domain, was revealed to effectively alleviate the severity and pathological damage associated with experimental autoimmune encephalo ...[more]

PMID: 31611942

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Project description:Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.Induction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-? receptor under the human glial fibrillary acidic protein promoter (GFAP?R1?) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAP?R1? mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.More severe and enlarged demyelinating lesions in GFAP?R1? compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1+Olig2+ OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAP?R1? both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAP?R1? mice, supporting inhibitory effects of ET-1 on OPC maturation.Our data implicate that IFN? signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.

Dataset Information

Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells.

Publications

Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells.

Similar Datasets

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