Extracellular Histones Associate with Blood–Brain Barrier Disruption and Astrocyte-Mediated Neuroinflammation During Polymicrobial Sepsis

Histones, normally confined to nucleosomes, are released into the bloodstream during sepsis due to cell damage and NETosis, contributing to organ dysfunction. In sepsis-associated encephalopathy (SAE), histones may worsen neurological outcomes. Using a cecal ligation and puncture (CLP)-induced polymicrobial sepsis model, we evaluated histone release, blood-brain barrier (BBB) disruption, complement activation, and glial responses in the brain. Immunofluorescence revealed histone accumulation and increased soluble histone levels in the brain 8-24 h post-CLP. BBB permeability increased, confirmed by FITC-inulin and Texas Red-dextran clearance assays. Complement activation, along with increased GFAP-positive astrocytes and Iba1-positive microglia, occurred post-CLP. Histones were detected in astrocytes and microglia. In vitro, stimulated astrocytes released histones upon activation and also demonstrated the ability to uptake extracellular FITC-labeled histones. Histone exposure elevated intracellular calcium levels and triggered cytokine secretion in astrocytes. Notably, histone stimulation activated the NLRP3 inflammasome, amplifying inflammation. These findings suggest that histone release during sepsis drives neuroinflammation, BBB disruption, and glial activation, positioning extracellular histones as potential therapeutic targets for sepsis-related brain manifestations like SAE.