Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis

TLDR

Gasdermin D is the key executor of pyroptosis, a proinflammatory cell death triggered by inflammasomes, but its role in neuroinflammation remains unclear. The study investigates whether GSDMD‑mediated pyroptosis underlies inflammatory demyelination in multiple sclerosis. The authors show that GSDMD activation in oligodendrocytes and microglia drives neuroinflammation and demyelination, and that pharmacologic caspase‑1 inhibition blocks pyroptosis, reducing demyelination and neurodegeneration, indicating a therapeutic avenue.

Abstract

Significance The pore-forming protein gasdermin D (GSDMD) was recently identified as the principal executioner of pyroptosis (“fiery death”), a type of proinflammatory programmed cell death driven by inflammasomes. Caspase-1 cleaves GSDMD, but whether this process contributes to neuroinflammation is unknown. Here, we report evidence of GSDMD-mediated pyroptosis as a primary mechanism of inflammatory demyelination in the central nervous system during multiple sclerosis (MS), a debilitating and incurable demyelinating disease that causes profound loss of myelin-forming oligodendrocytes. By identifying GSDMD induction and pyroptosis in oligodendrocytes and microglia, we discovered a previously unrecognized mechanism driving neuroinflammation and demyelination. Pharmacologically inhibiting caspase-1 prevented pyroptosis in experimental models of MS, reducing demyelination and neurodegeneration. These findings highlight therapeutic approaches for understanding and treating inflammatory demyelination.