ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2024; 20(2):733-750. doi:10.7150/ijbs.87646 This issue Cite
Research Paper
Pyroptotic Macrophage-Derived Microvesicles Accelerate Formation of Neutrophil Extracellular Traps via GSDMD-N-expressing Mitochondrial Transfer during Sepsis
1. Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.
2. The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong Province, 511518, China.
*These authors contributed equally to this work.
Abstract
Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the regulation of NETs formation during sepsis is unknown. Here, we showed that macrophages transfer mitochondria to neutrophils through microvesicles following pyroptosis; this process induces mitochondrial dysfunction and triggers the induction of NETs formation through mitochondrial reactive oxygen species (mtROS)/Gasdermin D (GSDMD) axis. These pyroptotic macrophage-derived microvesicles can induce tissues damage, coagulation, and NETs formation in vivo. Disulfiram partly inhibits these effects in a mouse model of sepsis. Pyroptotic macrophage-derived microvesicles induce NETs formation through mitochondrial transfer, both in vitro and in vivo. Microvesicles-mediated NETs formation depends on the presence of GSDMD-N-expressing mitochondria in the microvesicles. This study elucidates a microvesicles-based pathway for NETs formation during sepsis and proposes a microvesicles-based intervention measure for sepsis management.
Keywords: Pyroptosis, microvesicles, neutrophil extracellular traps, mitochondrial transfer, sepsis
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