Live or let die: Pyroptosis and inflammasome activation in glial cells during multiple sclerosis and experimental autoimmune encephalomyelitis

Abstract

Abstract Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18, and activate the pore-forming protein gasdermin-D (GSDMD). Recently, GSDMD was shown to be the primary executioner of pyroptosis, a lytic form of programmed cell death. Excessive GSDMD pore formation causes local osmotic swelling and eventual membrane lysis. Although evidence has emerged for inflammasome activation and pyroptosis in neurological diseases, the role of GSDMD in neuroinflammation remains uncharacterized. Multiple sclerosis (MS) is the prototypic inflammatory demyelinating disease of the central nervous system (CNS). We provide molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both macrophages/microglia and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the associated animal model, experimental autoimmune encephalomyelitis (EAE). We observe inflammasome activation, GSDMD expression, and pyroptosis in human microglia and ODCs in vitro inflammatory stimulation. Further, we demonstrate that both caspase-1 inhibition by the small molecule inhibitor VX-765 and GSDMD inhibition via siRNAs suppress pyroptosis in human microglia. VX-765 treatment of EAE animals reduced expression of inflammasome- and pyroptosis-associated proteins in the CNS, reduced neuroinflammation, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in multiple glial populations represents a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating neuroinflammation.