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Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.

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.

SUBMITTER: Silva CMS

PROVIDER: S-EPMC8703366 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.

Silva Camila Meirelles S CMS Wanderley Carlos Wagner S CWS Veras Flavio P FP Sonego Fabiane F Nascimento Daniele C DC Gonçalves Augusto V AV Martins Timna V TV Cólon David F DF Borges Vanessa F VF Brauer Verônica S VS Damasceno Luis Eduardo A LEA Silva Katiussia P KP Toller-Kawahisa Juliana E JE Batah Sabrina S SS Souza Ana Letícia J ALJ Monteiro Valter S VS Oliveira Antônio Edson R AER Donate Paula B PB Zoppi Daniel D Borges Marcos C MC Almeida Fausto F Nakaya Helder I HI Fabro Alexandre T AT Cunha Thiago M TM Alves-Filho José Carlos JC Zamboni Dario S DS Cunha Fernando Q FQ

Blood 20211201 25

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 m ...[more]

PMID: 34407544

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Project description:Traumatic brain injury (TBI) triggers a robust inflammatory response that is closely linked to worsened clinical outcomes. S100A8/A9, also known as calprotectin or myeloid-related protein-8/14 (MRP8/14), is an alarmin primarily secreted by activated neutrophils with potent pro-inflammatory property. In this study, we explored the roles of S100A8/A9 in modulating neuroinflammation and influencing TBI outcomes, delving into the underlying mechanisms. S100A8/A9-enriched neutrophils were present in the injured brain tissue of TBI patients, and elevated plasma levels of S100A8/A9 were correlated with poorer neurological function. Furthermore, using a TBI mouse model, we demonstrated that treatment with the selective S100A8/A9 inhibitor Paquinimod significantly mitigated neuroinflammation and neuronal death, thereby improving the prognosis of TBI mice. Mechanistically, we found that S100A8/A9, in conjunction with neutrophil activation and infiltration into the brain, enhances reactive oxygen species (ROS) production within neutrophils, accelerating PAD4-mediated neutrophil extracellular trap (NET) formation, which in turn exacerbates neuroinflammation. These findings suggest that S100A8/A9 amplifies neuroinflammatory responses by promoting NET formation in neutrophils. Inhibition of S100A8/A9 effectively attenuated NET-mediated neuroinflammation; however, when PAD4 was overexpressed in the brain using adenovirus, leading to an increased formation of NET in the brain, the anti-inflammatory effects of S100A8/A9 inhibition were markedly diminished. Further experiments with PAD4 knockout mice confirmed that the reduction of NETs could substantially alleviate S100A8/A9-driven neuroinflammation. Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI.

Dataset Information

Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.

Publications

Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.

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