Activation of Necroptosis in Multiple Sclerosis

TLDR

Multiple sclerosis is a CNS neurodegenerative disease marked by oligodendrocyte loss and demyelination, and the proinflammatory cytokine TNF‑α can trigger necroptosis through RIPK1/RIPK3 when caspase‑8 is deficient. We found that cortical lesions in MS exhibit defective caspase‑8 activation and robust necroptosis signaling (RIPK1, RIPK3, MLKL), share an increased insoluble proteome with other neurodegenerative diseases, and that RIPK1 inhibition protects oligodendrocytes from TNF‑α‑induced necroptosis in animal models and culture, indicating RIPK1 as a therapeutic target.

Abstract

Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS.