CD147 exacerbates ischemic brain injury and disrupts Wnt/β-catenin signaling and blood-brain barrier integrity

Abstract

Abstract Ischemic stroke is a leading cause of death and disability, with limited therapies beyond reperfusion. CD147 (Basigin), upregulated after cerebral ischemia, participates in neuroinflammation, however, its precise contributions to blood-brain barrier (BBB) disruption and neuronal injury are incompletely understood. Using a photothrombotic permanent middle cerebral artery occlusion (pMCAO) model in C57BL/6J male adult mice, we delivered CD147-overexpressing adenovirus (Ad Bsg) or control fluorophore adenovirus (Ad Fc) via intracerebroventricular injection. Infarct volume, neurological deficits, motor function, neuronal apoptosis, BBB integrity and hemorrhagic transformation were assessed. In vitro, HT22 neuronal cells were treated with recombinant Cyclophilin A (CyPA) to activate CD147 signaling. Wnt/β-catenin pathway activity was evaluated by western blot and qPCR. Using constitutively active β-catenin mice and pharmacological activation of AKT (using SC-79) were also performed. CD147 expression peaked at 24 h after stroke and correlated with infarct volume and neurological deficit severity. CD147 overexpression significantly increased infarct size, neuronal apoptosis, BBB leakage, brain edema, and downregulated the expression of claudin-5 and ZO-1. In neurons, CyPA-induced CD147 activation reduced p-AKT, p-GSK3β, β-catenin, and Wnt target gene expression. These effects were reversed by CD147 knockdown or by constitutively active β-catenin. CD147 exacerbates ischemic brain injury and BBB disruption by suppressing neuronal Wnt/β-catenin signaling through a mechanism involving the AKT/GSK3β node, supporting further evaluation of CD147-directed interventions after stroke.