Modulation of brain immune microenvironment and cellular dynamics in systemic inflammation.

Background: Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, affecting approximately 70% of patients, leading to increased mortality and long-term cognitive impairments among survivors. However, there is a lack of comprehensive studies on the development of SAE, especially related to the cellular communication networks in the brain microenvironment. Methods: We evaluated the impact of myeloid cells on the brain's immune microenvironment through glial cell alterations using bulk and single-cell transcriptomics data from human and mouse models and validated this with correlative experiments. We also developed the DeconvCellLink R package to study neuroinflammation-associated cellular interaction networks. A dynamic brain immune microenvironment map showing temporal alterations in brain cellular network during systemic inflammatory reactions was constructed using time-series data. Results: While brain cellular alterations differed between human and animal models, a highly conserved set of sepsis-associated genes regulating immune microenvironment signalling was identified. The dynamic alterations in cellular interaction networks and cytokines revealed brain immune cells' temporal response to systemic inflammation. We also found that valproic acid could mitigate sepsis-induced neuroinflammation by regulating glial cell balance and modulating the neuroimmune microenvironment. Conclusion: Through dynamic cellular communication networks, the study revealed that, immune dysregulation in the inflamed brain in SAE involves overactivation of innate immunity, with neutrophils playing a crucial role, providing a scientific framework for developing novel therapeutic strategies and offering new insights into the mechanisms underlying sepsis-induced brain dysfunction.