NLRP3/GSDMD-dependent neutrophil extracellular traps exacerbate microglia-mediated neuroinflammation following traumatic brain injury.

Traumatic brain injury (TBI) induces profound neuroinflammation, leading to secondary brain damage and neurological dysfunction. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in amplifying inflammatory responses after injury. This study investigates the involvement of the NLRP3 inflammasome and gasdermin D (GSDMD) in regulating NET formation and subsequent microglia-mediated neuroinflammation after TBI. Using a male mouse model of TBI, we demonstrate that activation of the NLRP3/GSDMD axis significantly enhances NET release from neutrophils. These NETs further activate microglia, promoting the secretion of proinflammatory cytokines, exacerbating blood-brain barrier damage, and worsening neurological deficits. Pharmacological inhibition of NLRP3 and GSDMD markedly attenuates NET formation, reduces microglial activation, and ameliorates neuroinflammation and neurological deficits. Collectively, our findings reveal a mechanistic pathway linking NLRP3/GSDMD-dependent NET formation with microglia-driven neuroinflammation, providing potential therapeutic targets for mitigating secondary injury following TBI.