Endothelial-specific Ezh2 deficiency exacerbates blood-brain barrier dysfunction and neuroinflammation in sepsis-associated encephalopathy
Abstract
Sepsis-associated encephalopathy (SAE) is a frequent yet insufficiently understood form of acute brain dysfunction driven by systemic inflammation and neurovascular injury. Here, we identify endothelial Enhancer of Zeste Homolog 2 (Ezh2) as a key epigenetic regulator that maintains blood-brain barrier (BBB) integrity and restrains neuroinflammatory responses during sepsis. Using constitutive and inducible endothelial-specific Ezh2 knockout mice, we demonstrate that loss of Ezh2 disrupts neurovascular unit organization at baseline, characterized by reduced tight junction protein expression, diminished glucose transporter levels, altered vascular morphology, and impaired astrocytic endfoot coverage. Following cecal ligation and puncture, Ezh2-deficient mice exhibited markedly increased mortality, exacerbated cerebral edema, and severe albumin extravasation, indicating profound BBB breakdown. Neuropathological analyses revealed region-dependent neuronal degeneration and apoptosis across cortex, midbrain, and hippocampus, accompanied by reactive gliosis and microglial activation. The absence of Ezh2 further promoted robust leukocyte infiltration, including neutrophils and CD4⁺/CD8⁺ T cells, into the cortex, basal ganglia, and choroid plexus, consistent with dysregulated peripheral-central nervous system (CNS) immune communication. Transcriptomic profiling identified upregulation of inflammatory, cytokine, and cell death pathways alongside downregulation of synaptic, metabolic,…
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