Exercise-driven glucocorticoid signaling acts as a systemic circuit breaker to reprogram microglia and resolve post-stroke inflammation

Following ischemic stroke, neuroinflammation drives severe secondary immunopathology, yet how systemic interventions coordinate peripheral and central immunity for neuroprotection remains elusive. Here, we demonstrate that acute-phase exercise accelerates motor rehabilitation and neural repair by activating the hypothalamic-pituitary-adrenal (HPA) axis to function as a potent systemic circuit breaker. Systemically, exercise-driven glucocorticoids, validated via targeted receptor blockade, induce profound spleen atrophy to restrict the peripheral immune pool, effectively depriving the ischemic brain of infiltrating leukocytes. By leveraging high-resolution single-cell transcriptomics, we identify microglia as the primary, highly sensitive central sensors of this glucocorticoid-mediated immunosuppression. These endocrine-reprogrammed microglia transition from a highly pro-inflammatory state toward a regulated, homeostatic quiescence. Mechanistically, they decisively blunt interferon (IFN) signaling to abrogate CXCL9/10-CXCR3 chemotaxis, attenuate antigen presentation and co-stimulation, thereby arresting the recruitment and in situ activation of effector T and B cells. Furthermore, this early suppression of neuroinflammation limits neural tissue damage, preserving the broader neuroglial niche in a quiescent, physiological state. Accordingly, the reactive repair signals typically provided by microglia to astrocytes and oligodendrocytes are substantially attenuated, underscoring that early protection from neuroinflammation effectively obviates the need for intense compensatory repair. Collectively, our findings delineate a novel systemic-to-central neuroimmune axis. By demonstrating how exercise harnesses systemic endocrine signals to interrupt the pathological inflammatory cascade, we highlight microglial glucocorticoid signaling as a precise therapeutic target for post-stroke neuroimmune modulation.