Journal
SCIENCE IMMUNOLOGY
Volume 3, Issue 26, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aat2738
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Funding
- NIH [T32 GM007250, P01HL029582, P01091222, R01086550]
- National Muscular Dystrophy Association [NMSS RG5130A2/1]
- National Multiple Sclerosis Society [RG-1707-28180]
- Harrington Discovery Institute fellowship
- [F31 NS 096857]
- [T32NS077888]
- [TL1 RR024991]
- [R01-EY014362]
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Dysregulation of inflammatory cell death is a key driver of many inflammatory diseases. Pyroptosis, a highly inflammatory form of cell death, uses intracellularly generated pores to disrupt electrolyte homeostasis and execute cell death. Gasdermin D, the pore-forming effector protein of pyroptosis, coordinates membrane lysis and the release of highly inflammatory molecules, such as interleukin-1D, which potentiate the overactivation of the innate immune response. However, to date, there is no pharmacologic mechanism to disrupt pyroptosis. Here, we identify necrosulfonamide as a direct chemical inhibitor of gasdermin D, the pyroptotic pore-forming protein, which binds directly to gasdermin D to inhibit pyroptosis. Pharmacologic inhibition of pyroptotic cell death by necrosulfonamide is efficacious in sepsis models and suggests that gasdermin D inhibitors may be efficacious clinically in inflammatory diseases.
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