Targeting the Microglia-Astrocyte OSM-OSMR Axis Restores Blood-Brain Barrier Integrity After Experimental Cerebral Ischemia-Reperfusion in Mice.

Abstract

Blood-brain barrier (BBB) disruption is a major contributor to brain injury following ischemic stroke. However, current endothelial-targeted strategies for BBB protection have shown limited clinical efficacy. Glial cells are essential for maintaining BBB integrity, but the mechanisms underlying glial-mediated BBB dysfunction after ischemic stroke remain poorly defined. Here, we identify microglial oncostatin M (OSM) and astrocytic OSM receptor (OSMR) as critical mediators of BBB disruption following cerebral ischemia-reperfusion. Single-cell RNA sequencing and immunofluorescence analysis revealed selective upregulation of OSMR in astrocytes after transient middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. Astrocyte-specific OSMR knockdown maintained BBB integrity by restoring aquaporin-4 polarity and tight junction protein expression in electron microscopy and dextran leakage assays, thereby reducing infarct volume and improving neurological function. To elucidate the underlying mechanism, cell-cell communication analysis and proximity ligation assays demonstrated a direct and enhanced interaction between microglial OSM and astrocytic OSMR after MCAO/R. Similarly, OSM was markedly upregulated in microglia, and microglia-specific OSM knockout reproduced the protective effects of astrocytic OSMR knockdown, thereby restoring BBB integrity. Collectively, these results support the OSM-OSMR axis as a potential therapeutic target for the preservation of BBB integrity in ischemic stroke.