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.
Inflammatory bowel disease (IBD) is a multifactorial chronic disease, commonly associated with alteration in the composition and function of gut microbiota. This process can lead to a decreased production of short chain fatty acids (SCFAs) by the gut microbiota, mainly butyrate, which is an important immunomodulatory molecule in the intestine. Butyrogenic bacteria normally produces butyrate through carbohydrate fermentation or amino acids degradation pathways. This molecule plays an important protective role in intestinal homeostasis acting in both adaptive immunity and innate immunity. This review summarizes the current knowledge about the role of butyrate on the development of IBD and the protective mechanisms of this metabolite on the intestinal mucosa and the whole body, as reported by in vitro and in vivo studies. Thus, butyrate can regulate the activation of regulatory T cells, increasing the acetylation of histones and decreasing the activation of NF-κB. In addition, it can also stimulate the mucus production from epithelial cells and the rearrangement of tight junction proteins.
Background The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear. Objectives We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19. Methods We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection. Results We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage. Conclusion These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear. Using a single-cell transcriptome analysis we observed that the expression of GSDMD and inflammasome-related genes were increased in neutrophils from COVID-19 patients. Furthermore, high expression of GSDMD was found associated with NETs structures in the lung tissue of COVID-19 patients. The activation of GSDMD in neutrophils requires live SARS-CoV-2 and occurs after neutrophil infection via ACE2 receptors and serine protease TMPRSS2. In a mouse model of SARS-CoV-2 infection, the treatment with GSDMD inhibitor (disulfiram) reduced NETs release and organ damage. These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology, and suggests that GSDMD inhibitors, can be useful to COVID-19 treatment.
Sepsis is characterized by a dysregulated immune response to infection characterized by an early hyperinflammatory and oxidative response followed by a subsequent immunosuppression phase. Although there have been some advances in the treatment of sepsis, mortality rates remain high, urging for the search of new therapies. β-Lapachone (β-Lap) is a natural compound obtained from Tabebuia avellanedae Lorentz ex Griseb. with several pharmacological properties including bactericidal, anti-inflammatory, and antioxidant activity. Thus, the aim of this study was to evaluate the effects of β-Lap in a mouse sepsis model. To this, we tested two therapeutic protocols in mice submitted to cecal ligation and puncture- (CLP-) induced sepsis. First, we found that in pretreated animals, β-Lap reduced the systemic inflammatory response and improved bacterial clearance and mouse survival. Moreover, β-Lap also decreased lipid peroxidation and increased the total antioxidant capacity in the serum and peritoneal cavity of septic animals. In the model of severe sepsis, the posttreatment with β-Lap was able to increase the survival of animals and maintain the antioxidant defense function. In conclusion, the β-Lap was able to increase the survival of septic animals by a mechanism involving immunomodulatory and antioxidant protective effects.
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