NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy.

Microglia are critical in the neuroinflammatory cascade of sepsis-associated encephalopathy (SAE), yet their functional heterogeneity and transcriptional regulators remain poorly characterized. Here, through single-cell RNA sequencing (scRNA-seq) of murine brains post-cecal ligation and puncture (CLP)-induced sepsis, we resolved six microglial clusters. Notably, a subset of inflammasome-activated microglia emerged as a driver for neuroinflammation and cognitive impairment, with marked upregulation of Nlrp3, Il1b, Tnf and enriched pathways for interleukin-1β (IL-1β) production and neuron death. Transcriptional profiling of the cluster highlighted nucleoside diphosphate kinase 2 (NME2) as a marker transcription factor, with its expression and nuclear localization dynamically upregulated post-CLP. Mechanistically, NME2 directly bound the Nlrp3 promoter and recruited enhancer of polycomb homolog 2 (EPC2), a component of the NuA4 histone acetyltransferase complex, to induce H2AK5 acetylation and chromatin remodeling, thereby enhancing Nlrp3 transcription. Conditional knockout of Nme2 in microglia or pharmacological inhibition using stauprimide significantly decreased cerebrospinal fluid IL-1β, attenuated neuronal cell death, and rescued both working memory and recognition memory in septic mice. These findings identify NME2 as a critical transcription regulator of inflammasome-activated microglial lineage dynamics through epigenetic control of NLRP3, offering a mechanistic rationale for targeting the NME2-EPC2 axis to mitigate sepsis-induced cognitive impairment.