| Literature DB >> 34407544 |
Camila Meirelles S Silva1,2,3, Carlos Wagner S Wanderley1,2,3, Flavio P Veras1, Fabiane Sonego1, Daniele C Nascimento1,2,3, Augusto V Gonçalves1,4, Timna V Martins1,2, David F Cólon1,2, Vanessa F Borges1,3, Verônica S Brauer2, Luis Eduardo A Damasceno1,2, Katiussia P Silva1,5, Juliana E Toller-Kawahisa1, Sabrina S Batah6, Ana Letícia J Souza3, Valter S Monteiro1,2, Antônio Edson R Oliveira1, Paula B Donate1,3, Daniel Zoppi7, Marcos C Borges7, Fausto Almeida2, Helder I Nakaya1,8, Alexandre T Fabro6, Thiago M Cunha1,3, José Carlos Alves-Filho1,3, Dario S Zamboni1,4, Fernando Q Cunha1,3.
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.Entities:
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Year: 2021 PMID： 34407544 PMCID： PMC8703366 DOI： 10.1182/blood.2021011525
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 25.476