PerspectiveImmunology

Rescue from a fiery death: A therapeutic endeavor

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Science  08 Nov 2019:
Vol. 366, Issue 6466, pp. 688-689
DOI: 10.1126/science.aaw1177

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Summary

Cells die in many ways. Apoptosis is an immunologically silent cell death program that is important for embryonic development. By contrast, pyroptosis is a proinflammatory mode of cell death that is triggered by diverse infectious and sterile insults. Many cell types are pyroptosis-competent, including hematopoietic, epithelial, and endothelial cells. Inhibiting pyroptosis ameliorates disease, including septic shock and autoinflammation, in multiple preclinical mouse models. Thus, attenuating aberrant or excessive pyroptosis may be clinically beneficial, despite a role of pyroptosis in pathogen defense. Pyroptosis is driven by the pore-forming fragment of the gasdermin D (GSDMD) protein, which is proteolytically generated by the cysteine protease caspases 1, 4, 5, and 11 in response to activation of the inflammasome (a multiprotein complex that detects infectious and sterile insults). Recent clinical findings emphasize the critical role of pyroptosis in human inflammatory disease and cancer, and this has galvanized focus on GSDMD as a therapeutic target.

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