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Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.
- Source :
-
Blood [Blood] 2021 Dec 23; Vol. 138 (25), pp. 2702-2713. - Publication Year :
- 2021
-
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.<br /> (© 2021 by The American Society of Hematology.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 138
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 34407544
- Full Text :
- https://doi.org/10.1182/blood.2021011525