Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation

Blood-brain barrier (BBB) disintegration emerges as a significant contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we examined the potential role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Systemic lipopolysaccharide administration caused an NLRP3-dependent increase in BBB permeability and myeloid cell infiltration into the brain. Using a cell-specific, hyperactive NLRP3-expressing mouse model, we found that microglial NLRP3 activation is crucial for peripheral inflammation-induced BBB disruption. In contrast, NLRP3 and microglial gasdermin D (GSDMD) deficiency remarkably attenuated lipopolysaccharide-induced BBB breakdown. Notably, IL-1 was unnecessary for this NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis specifically upregulates CXCL chemokine around BBB via producing GDF-15, recruiting Cxcr2-containing neutrophils into the brain. Neutrophil depletion and Cxcr2 blockade significantly reduced NLRP3-mediated BBB impairment. Collectively, our findings unveiled the significant role of NLRP3-driven chemokine production for BBB disintegration, suggesting a potential therapeutic target to mitigate neuroinflammation.