Center for Research in Inflammatory Diseases.
Department of Biochemistry and Immunology.
Blood. 2021 Dec 23;138(25):2702-2713. doi: 10.1182/blood.2021011525.
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.
多器官功能障碍是脓毒症进展的最严重后果，与预后不良高度相关。过多的中性粒细胞胞外诱捕网（NETs）是脓毒症期间发生器官衰竭的关键因素。因此，针对 NET 释放的干预措施可能会有效预防与这种疾病相关的基于 NET 的器官损伤。在此，我们证明了在脓毒症患者和小鼠的中性粒细胞中，孔形成蛋白 GSDMD（gasdermin D）是活跃的，并且在 NET 释放中起着关键作用。用二硫苏糖醇抑制 GSDMD 或基因缺失会阻断 NET 的形成，从而减少多器官功能障碍和脓毒症的致死率。从机制上讲，我们证明在脓毒症期间，caspase-11/GSDMD 途径的激活控制了中性粒细胞在脓毒症期间 NET 的释放。总之，我们的发现为二硫苏糖醇的新治疗用途提供了依据，并表明 GSDMD 是改善脓毒症治疗的一个治疗靶点。
