1. Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.
- Author
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Silva CMS, Wanderley CWS, Veras FP, Sonego F, Nascimento DC, Gonçalves AV, Martins TV, Cólon DF, Borges VF, Brauer VS, Damasceno LEA, Silva KP, Toller-Kawahisa JE, Batah SS, Souza ALJ, Monteiro VS, Oliveira AER, Donate PB, Zoppi D, Borges MC, Almeida F, Nakaya HI, Fabro AT, Cunha TM, Alves-Filho JC, Zamboni DS, and Cunha FQ
- Subjects
- Acetaldehyde Dehydrogenase Inhibitors therapeutic use, Adoptive Transfer, Aged, Animals, Cells, Cultured, Disulfiram therapeutic use, Female, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Male, Mice, Inbred C57BL, Middle Aged, Multiple Organ Failure pathology, Multiple Organ Failure therapy, Phosphate-Binding Proteins antagonists & inhibitors, Sepsis pathology, Sepsis therapy, Mice, Extracellular Traps genetics, Gene Deletion, Intracellular Signaling Peptides and Proteins genetics, Multiple Organ Failure genetics, Phosphate-Binding Proteins genetics, Sepsis genetics
- Abstract
Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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