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 stress with necroptosis inhibitors19. Jurewicz et al. found that TNF treatment of human OLs in culture induces apoptosis-inducing factor mitochondria associated 1 (AIF)-mediated cell death, also known as parthanatosis, involving hyperactivation of DNA damage response machinery54. TNFα was also shown to induce human OL progenitor cells to undergo death by pyroptosis, a pro-inflammatory programmed cell death mediated by inflammasome complex activation55. OLs in MS lesions were shown to express a pyroptosis mediator, gasderminD (GSDMD), and inflammasome inhibition reduces injury to the OL lineage in EAE55. Hypoxia, a feature of a subtype of MS lesions35, can induce GSDMD expression through phosphorylation of STAT3, which promotes nuclear translocation of programmed death ligand 1 (PDL1)56.
