Necroptosis is a form of necrosis that depends on a membrane pore-forming complex termed the necroptosome. Necroptosis is usually triggered via Toll-like receptors or death receptors that include TNF receptor-1 (TNFR1)49 acting via RIPK1 to sequentially activate RIPK3 and MLKL. Ofengeim et al. (2015) implicated activation of the necroptosis pathway as contributing to progressive MS, finding that ~50% genes upregulated in chronic active lesions are regulators of this process50. Necroptosome markers RIPK1 and MLKL were expressed in OLs and microglia, in MS lesions, the latter consistent with our findings of RIPK3+ and MLKL + microglia in remyelinating MS lesions51. Ripk3−/− mice had increased resistance to cuprizone-induced demyelination, and OLs derived from these mice were less susceptible to TNF-α-mediated necroptosis50. However, Zhang et al. found that cuprizone-induced injury reflected an MLKL-dependent, but RIPK3-independent, mechanism of injury acting via myeloid cells52. Zelic et al. then showed that RIPK1 activation in microglia and astrocytes induces a detrimental neuroinflammatory program that contributes to the neurodegenerative environment in progressive MS53. Of note, we could not inhibit cell death in human mature OLs exposed to metabolic
