Abstract
Background: Subarachnoid hemorrhage (SAH) is a critical cerebrovascular disease with high mortality and morbidity. Despite advances in treatments that have reduced mortality, survivors frequently suffer from persistent cognitive dysfunction. Border-associated macrophages (BAMs) play essential nutritional and immunoregulatory roles in neurological diseases; however, their dynamic alterations following SAH and their effects on cognitive outcomes remain unclear. Remote ischemic postconditioning (RIPostC) is an emerging neuroprotective approach, but its mechanisms in the context of SAH have not been fully elucidated. This study aimed to investigate the role of BAMs in cognitive dysfunction after SAH and to explore the effects and underlying mechanisms of RIPostC intervention. Methods: A mouse model of SAH was established and combined with multiomics analyses to systematically assess the spatiotemporal changes in BAMs during the subacute phase after SAH and their relationship with cognitive dysfunction. The effects of RIPostC on BAMs abundance, immunoregulatory function, and cognitive outcomes were evaluated. The molecular mechanisms were further examined using chimeric bone marrow (BM) mice. Results: In the subacute phase following SAH, BAMs abundance was reduced and correlated with the severity of myelin damage and cognitive impairment. RIPostC treatment significantly increased BAMs abundance, promoted myelin regeneration, and improved cognitive function. Mechanistically, RIPostC induced amino acid metabolic reprogramming in BAMs via the IL-33/ST2 axis, thereby increasing the proliferation, migration, and myelination of oligodendrocyte precursor cells (OPCs). These beneficial effects were markedly diminished in WT/ST2 KO chimeric mice. Conclusion: This study demonstrates the critical involvement of BAMs in cognitive dysfunction after SAH and shows that RIPostC ameliorates cognitive deficits by modulating BAMs through the IL-33/ST2 axis. These findings provide new insights into the pathophysiology of SAH, support targeted interventions involving BAMs and the IL-33/ST2 axis, and offer important evidence for the clinical translation of RIPostC as a safe and noninvasive therapeutic strategy for SAH.