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

Area of Science:

• Immunology
• Pathophysiology
• Pharmacology

Background:

• Sepsis-induced multiple organ dysfunction is a severe complication linked to poor outcomes.
• Neutrophil extracellular traps (NETs) significantly contribute to organ failure during sepsis progression.
• Targeting NET release presents a promising strategy for preventing sepsis-related organ injury.

Purpose of the Study:

• To investigate the role of gasdermin D (GSDMD) in neutrophil extracellular trap (NET) formation during sepsis.
• To evaluate the therapeutic potential of inhibiting GSDMD in sepsis models.

Main Methods:

• Assessed GSDMD activation in neutrophils from septic humans and mice.
• Utilized disulfiram to inhibit GSDMD and genetic deletion to abrogate NET formation.
• Measured the impact of GSDMD inhibition on multiple organ dysfunction and sepsis lethality.

Main Results:

• Gasdermin D (GSDMD) was found to be active in neutrophils during sepsis and crucial for NET release.
• Inhibition of GSDMD, via disulfiram or genetic deletion, significantly reduced NET formation.
• GSDMD inhibition led to decreased multiple organ dysfunction and improved survival rates in sepsis models.

Conclusions:

• The caspase-11/GSDMD pathway is a key regulator of NET release by neutrophils in sepsis.
• Disulfiram demonstrates potential as a novel therapeutic agent for sepsis by inhibiting GSDMD.
• GSDMD represents a viable therapeutic target for improving outcomes in sepsis treatment.