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Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice
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Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice
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Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice
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Journal Article
Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice
2025
Overview
Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation.
The biological mechanisms regulating blood-brain barrier integrity remain unclear. Here, the authors identify microglial NLRP3-gasdermin D signaling as a driver of blood-brain barrier disruption during peripheral inflammation in mice, mediated by CXCL-dependent neutrophil recruitment.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/21
/ 13/31
/ 13/51
/ 14/19
/ 14/69
/ 38/77
/ 38/91
/ 82/58
/ Animals
/ Blood-Brain Barrier - immunology
/ Blood-Brain Barrier - metabolism
/ Blood-Brain Barrier - pathology
/ Humanities and Social Sciences
/ Interleukin-1beta - metabolism
/ Intracellular Signaling Peptides and Proteins - genetics
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Male
/ Mice
/ NLR Family, Pyrin Domain-Containing 3 Protein - genetics
/ NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
/ Phosphate-Binding Proteins - genetics
/ Phosphate-Binding Proteins - metabolism
/ Receptors, Interleukin-8B - metabolism
/ Science
