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Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6065-E6074. doi: 10.1073/pnas.1722041115. Epub 2018 Jun 12.

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

Author information

1
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
2
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada.
3
Department of Immunology, Tehran University of Medical Sciences, Tehran 1417653761, Iran.
4
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
5
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
6
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada.
7
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada; chris.power@ualberta.ca.

Abstract

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. 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). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODCs in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.

KEYWORDS:

EAE; gasdermin D; inflammasome; multiple sclerosis; pyroptosis

PMID:
29895691
PMCID:
PMC6042136
DOI:
10.1073/pnas.1722041115
[Indexed for MEDLINE]
Free PMC Article

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