Gasdermin E exerts pleiotropic effects in glia and axons during inflammatory demyelination: implications for progressive multiple sclerosis

The inflammasome-pyroptosis axis represents a cellular cascade driving innate immune responses and culminating in regulated cell death. The gasdermins are proteins that participate in inflammatory regulated cell death. Nonetheless, there is increasing evidence that gasdermins contribute to other cellular processes including neoplasia, immunity, and development. Gasdermin E (GSDME) participates in multiple cellular functions although its constitutive effects in central nervous system (CNS) cells are uncertain. Using a multiplatform approach, we investigated GSDME’s expression and functions within the CNS of persons with progressive multiple sclerosis (PwPMS) and in the cuprizone (CPZ) mouse model of inflammatory demyelination that was analysed in terms of neurobehavioral performance, morphological, molecular, as well as metabolic changes assessed by [ 18 F]FDG positron emission tomography neuroimaging. In cerebral tissues from PwPMS, GSDME expression was significantly increased in brain macrophages (BMs) compared to matched nonMS tissues, especially at the margin of demyelinating lesions. This finding coincided with perturbed expression of mitochondria-related proteins in PwPMS brain tissues. In differentiated human macrophage-like cells, deletion of GSDME resulted in altered mitochondrial protein expression and reduced mitochondrial activity. In mice exposed to CPZ, Gsdme +/+ mice showed increased Gsdme expression in BMs and inflammatory demyelination, while Gsdme −/− mice displayed significantly increased axonal degeneration with hyperactivated BMs in demyelinated sites and disrupted mitochondria-associated protein expression. CPZ exposure significantly reduced CNS [ 18 F]FDG uptake accompanied by worsened motor impairments in Gsdme −/− mice, compared to exposed Gsdme +/+ mice. GSDME expression increases during disease-mediated stresses although its absence exacerbates BM activation and associated axonal injury, likely through altered mitochondrial functions, during inflammatory demyelination.