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

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.

Authors:   Brienne A. McKenzie; Manmeet K. Mamik; Leina B. Saito; Roobina Boghozian; Maria Chiara Monaco; Eugene O. Major; Jian-Qiang Lu; William G. Branton; Christopher Power
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   26
Year:   2018
Pages:   E6065
DOI:   10.1073/pnas.1722041115
Publication date:   26-Jun-2018
Facts, background information, dossiers
  • neuroinflammation
  • oligodendrocytes
  • neurodegeneration
More about Proceedings of the National Academy of Sciences
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