Research ArticleCELL DEATH

Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis

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Science Immunology  24 Aug 2018:
Vol. 3, Issue 26, eaat2738
DOI: 10.1126/sciimmunol.aat2738

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  • RE: Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis
    • Dianne Sika-Paotonu, Associate Dean (Pacific)/Senior Lecturer Pathology & Molecular Medicine, Wellington School of Medicine & Health Sciences, University of Otago, New Zealand

    To the Editor,

    I read with keen interest the article prepared by Rathkey J.K, et al (1) and entitled: “Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis.”

    This work showed that Gasdermin D (GSDMD)-the pore forming effector protein of the Pyroptosis pathway, co-ordinates membrane lysis and the release of highly inflammatory molecules such as IL-1B which potentiates over-activation of the immune response.

    Chemical inhibition of the Pyroptosis is achieved using Necrosulfonamide (NSA) a direct chemical inhibitor that binds to the GSDMD protein blocking the Pyroptosis cell death pathway without interfering with TLR signalling, inflammasome formation and other innate cell death pathways.

    In the sepsis model described where lethal doses of LPS were administered to murine participants, it was noticed that although survival benefit with NSA administration was achieved, this effect involved the administration of NSA 30 mins before TLR 4 agonist administration in the single NSA dose and double NSA dose recipient cohorts.

    Enough prior warning to support administration of NSA in time before the onset of sepsis in the clinical setting could be problematic.

    The authors highlight that this research work presents evidence to support NSA as being a potential lead compound, with the need for more potent derivatives to be developed for therapeutic utility.

    A set of elegant...

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    Competing Interests: None declared.

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