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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263094 | GEO | 2024/12/30

REPOSITORIES: GEO

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

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

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