Abstract

Acute-phase neuroinflammation and early brain injury progressing rapidly is responsible for substantial severity and mortality in subarachnoid hemorrhage (SAH). While cohort studies have confirmed that aerobic exercise (AE) was associated with decreased short-term mortality, its precise mechanisms remain elusive. We employed a murine SAH model subjected to preconditioning AE to validate the above hypothesis, combining early neurological function assessment and histological staining. Whole-transcriptome profiling and single-cell RNA sequencing were performed to capture differentially expressed genes and to delineate subtype-specific differentiation. To recapitulate the neuroimmune crosstalk in vitro, we established a primary neutrophil–microglia coculture system. Targeted receptor–ligand interaction studies were employed to validate the specific environmental variables driving their synergistic activation. Our data indicated that AE significantly ameliorated neurological outcomes, cerebral edema, and neuronal apoptosis post-SAH. Sequencing data identified classical pro-inflammatory M1-like microglia, alongside a novel early-response microglial subset characterized by high expression of transforming growth factor beta 1; both populations were regulated by AE for modulating neuroinflammation and significantly correlated with infiltrating neutrophil counts. This crosstalk was mediated by mature neutrophil-derived leucine-rich alpha-2-glycoprotein 1 (Lrg1), which differentially activated the microglial transforming growth factor beta signaling pathway. Collectively, AE-mediated suppression of neutrophil infiltration rebalanced microglial differentiation, thereby attenuating neuroinflammation following SAH. We identified Lrg1 as a key immune mediator in this process, highlighting exercise-induced reprogramming at the receptor level as a potential therapeutic strategy for SAH.