Lactate exacerbates neuroinflammation in sepsis-associated encephalopathy via promoting neutrophil migration from skull bone marrow to the meninge

Abstract

Sepsis-associated encephalopathy (SAE) is one of the most common and severe complications of sepsis. Although lactate and neutrophils play pivotal roles in SAE, the mechanisms linking lactate, neutrophils, and neuroinflammation in SAE remain largely unclear.

In this study, SAE model was induced in C57BL/6 J mice via intraperitoneal lipopolysaccharide (LPS) injection, with lactate production inhibited by administering the lactate dehydrogenase inhibitor FX-11. Neutrophils were visualized by immunofluorescence, and immune cell subsets were quantified via flow cytometry. Our findings revealed that lactate levels in the skull bone marrow (SBM) were significantly elevated in SAE mice, accompanied by decreased SBM neutrophils and increased neutrophil extravasation into the meninges. These effects were reproduced in exogenous lactate-administered normal mice. Further studies identified that a CD31⁺ channel between the SBM and meninges facilitates neutrophil mobilization and migration. Notably, FX-11 injection significantly alleviated SAE in mice, as indicated by reduced SBM lactate production, inhibited neutrophil mobilization, decreased meningeal neutrophil extravasation, suppressed microglial activation and reduced hippocampal inflammatory cytokines as well.

In summary, our results show that elevated lactate levels in the SBM promote neutrophil migration between the skull and meninges and hence exacerbate SAE neuroinflammation, which can be potently improved in the presence of the lactate inhibitor FX-11. The migration of neutrophils influenced by lactate in the skull–meninges–brain axis could be a potential therapeutic target for the treatment of SAE.