Pyroptotic Macrophage-Derived Microvesicles Accelerate Formation of Neutrophil Extracellular Traps via...

Area of Science:

• Immunology
• Cell Biology
• Pathophysiology

Background:

• Sepsis involves macrophage pyroptosis and neutrophil extracellular traps (NETs).
• The link between macrophage pyroptosis and NETs formation in sepsis remains unclear.

Purpose of the Study:

• To investigate the role of macrophage pyroptosis in regulating NETs formation during sepsis.
• To elucidate the underlying mechanisms of microvesicle-mediated NETs induction.

Main Methods:

• In vitro and in vivo experiments using a mouse model of sepsis.
• Analysis of mitochondrial transfer from pyroptotic macrophages to neutrophils via microvesicles.
• Assessment of the role of mitochondrial reactive oxygen species (mtROS) and Gasdermin D (GSDMD) axis.

Main Results:

• Pyroptotic macrophages transfer mitochondria to neutrophils through microvesicles.
• This transfer induces mitochondrial dysfunction and triggers NETs formation via the mtROS/GSDMD pathway.
• Pyroptotic macrophage-derived microvesicles promote tissue damage and coagulation in vivo.
• Disulfiram partially inhibits these sepsis-associated effects in mice.

Conclusions:

• Macrophage pyroptosis-derived microvesicles mediate NETs formation through mitochondrial transfer.
• This pathway is dependent on GSDMD-N-expressing mitochondria within microvesicles.
• Identified a novel microvesicle-based pathway for NETs formation in sepsis, suggesting potential therapeutic interventions.