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.

Gasdermin-D activation by SARS-CoV-2 trigger NET and mediate COVID-19 immunopathology

“…This window of therapy with disulfiram was sufficient to reduce NETs concentration, cytokine storm, and attenuate important tissues damages in several organs. Similarly, we observed that the inhibition of GSDMD by disulfiram in the sepsis model efficiently abrogates NETosis, systemic inflammation, and vital organs dysfunction, improving mice survival (Silva et al, 2021). Of note, the course of the disease in the mouse model is different when compared to humans, in which the symptoms are observed on 5-6 days after the infection and maintained for around 14 days (Zhou et a., 2020).…”

“…However, a study showed that disulfiram at nanomolar concentration covalently binds and modifies human/mouse Cys191/Cys192 in GSDMD inhibiting its poreforming function (Hu et al, 2020). Furthermore, we recently demonstrated that inhibition of GSDMD by disulfiram prevents neutrophil death by NETosis (Silva et al, 2021). Considering this finding, we tested the effect of disulfiram on the COVID-19 experimental model.…”

“…The N-terminal (GSDMD-NT) oligomerizes with plasma and nuclear membranes, forming membranes pores that mediate cell death by NETosis (Sollberger et al, 2018;Chen et al, 2018;Kambara et al, 2018;Broz et al, 2020). During sepsis, the genetic deletion or pharmacological inhibition of GSDMD with disulfiram prevented the formation of NETs, protecting mice from organ damage development and increasing survival (Silva et al, 2021). Disulfiram is a drug that inhibits aldehyde dehydrogenase (ALDH) and is used to treat alcoholism (Koppaka et al, 2012).…”

Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19)

“…(1) Caspase1/4/11 and gasdermin D (GSDMD) in pyroptosis are required by NETosis and contribute to cytolysis. Presently, three research groups indicated that the pore-forming protein GSDMD cleaved by Caspase 11 is essential for NET release [184] , [185] , [186] . Moreover, Ang II-induced spleen tyrosine kinase (SYK) activates inflammasome activation [187] , [188] , [189] .…”

Fracture healing is delayed in the absence of gasdermin signaling

“…Mice lacking GSDMD are protected against multi-organ damage caused by gain-of-function mutations of nucleotide-binding oligomerization domain-like receptors family, pyrin domain containing 3 (NLRP3) or pyrin inflammasome (26,27). GSDMD is also involved in the pathogenesis of complex diseases including experimental autoimmune encephalitis, radiation-induced tissue injury, ischemia/reperfusion injury, sepsis, renal fibrosis, and thrombosis (28)(29)(30)(31)(32)(33). Other well studied GSDMs include GSDMA and GSDME (25,(34)(35)(36).…”