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

Summary

Using scRNA-seq after CLP-induced sepsis, the authors identify an inflammasome-activated microglial subset driving neuroinflammation and cognitive deficits. NME2 binds the Nlrp3 promoter, recruits EPC2 to induce H2AK5 acetylation, and enhances Nlrp3 transcription; genetic or pharmacologic NME2 inhibition reduces IL-1β, neuronal death, and rescues memory in septic mice.

Key Findings

• scRNA-seq resolved six microglial clusters post-CLP; an inflammasome-activated subset upregulated Nlrp3, Il1b, and Tnf.
• NME2 directly bound the Nlrp3 promoter, recruited EPC2, and induced H2AK5 acetylation to amplify Nlrp3 transcription.
• Microglia-specific Nme2 knockout or stauprimide treatment lowered CSF IL-1β, reduced neuronal death, and rescued working and recognition memory.

Clinical Implications

Although preclinical, targeting microglial epigenetic regulation of NLRP3 (e.g., NME2 inhibition) could form the basis for neuroprotective interventions in sepsis-associated encephalopathy; human validation and safety studies are needed.

Limitations

• Findings are based on murine models; human microglial validation is lacking
• Potential off-target effects of stauprimide and limited temporal profiling

Future Directions

Validate NME2–EPC2–NLRP3 axis in human post-mortem/CSF samples, develop selective NME2 modulators, and test neurocognitive endpoints in translational sepsis models.