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Updated: Jul 15, 2025
Visualization of Neutrophil Extracellular Traps in Mesenteric Venules After Mesenteric Ischemia-Reperfusion Injury via Intravital Microscopy
Published on: September 27, 2024
GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion
Chen Zhao1,2,3,4, Fangte Liang1,2,3,4, Mengling Ye5
1Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China.
Abstract:
Lung ischemia/reperfusion injury (LIRI) is a complex pathophysiological process, with the histopathological hallmark of neutrophils migrating into the lungs. Neutrophil extracellular traps (NETs) have been suggested to exert a critical role in the pathogenesis of inflammation and infection in humans and animals, while the exact functions and underlying mechanisms of NETs in LIRI remain insufficiently elucidated. In this study, we investigated the role of pore-forming protein gasdermin D (GSDMD) on NETs release in LIRI induced by lung ischemia/reperfusion (I/R). We found that disulfiram, a GSDMD inhibitor, dramatically reduced NETs release and pathological injury in lung I/R in vivo and in vitro. Additionally, GSDMD caused mitochondrial DNA (mtDNA) leaking into the neutrophil cytosol, and then the cytoplasmic mtDNA activated the cGAS-STING signaling pathway and stimulated NETs formation in lung I/R. Furthermore, inhibition of cGAS/STING pathway could inhibit cytosol mtDNA mediated NETs formation.
Insights
Gasdermin D (GSDMD) drives neutrophil extracellular trap (NET) release in lung ischemia/reperfusion injury (LIRI). Inhibiting GSDMD or the cGAS-STING pathway reduces NET formation and lung damage in LIRI.
Area of Science:
- Immunology
- Pathophysiology
- Molecular Biology
Background:
- Lung ischemia/reperfusion injury (LIRI) involves neutrophil migration.
- Neutrophil extracellular traps (NETs) are implicated in LIRI, but mechanisms are unclear.
Purpose of the Study:
- Investigate the role of gasdermin D (GSDMD) in NET release during LIRI.
- Elucidate the molecular pathways linking GSDMD to NET formation in LIRI.
Main Methods:
- Utilized in vivo and in vitro models of lung ischemia/reperfusion (I/R).
- Administered disulfiram, a GSDMD inhibitor.
- Assessed NET release and pathological injury.
- Examined mitochondrial DNA (mtDNA) translocation and cGAS-STING pathway activation.
Main Results:
- Disulfiram significantly reduced NET release and lung injury in LIRI models.
- GSDMD promoted mitochondrial DNA (mtDNA) leakage into neutrophil cytosol.
- Cytoplasmic mtDNA activated the cGAS-STING signaling pathway, stimulating NET formation.
- Inhibition of the cGAS-STING pathway blocked mtDNA-mediated NET formation.
Conclusions:
- GSDMD plays a critical role in initiating NET formation during LIRI.
- The GSDMD-mtDNA-cGAS-STING axis is a key pathway driving LIRI pathogenesis.
- Targeting GSDMD or the cGAS-STING pathway offers potential therapeutic strategies for LIRI.
