Reperfusion enhances treg-mediated neuroprotection and IL-10 signaling in a mouse model of large vessel occlusion

The indications for acute reperfusion therapies in ischemic stroke have recently expanded to include patients with large ischemic cores, highlighting an urgent need for targeted neurotherapeutics that maximize tissue salvage. Preclinical studies suggest that early reperfusion, even after extensive ischemic injury, can mitigate infarct expansion and activate endogenous regenerative pathways, though the precise mechanisms driving these therapeutic benefits remain incompletely understood. In this study, we investigated the cellular and molecular mechanisms underlying successful reperfusion to identify novel avenues for immunotherapy. Using transient (t-MCAO) and permanent (p-MCAO) middle cerebral artery occlusion mouse models, we comprehensively analyzed central and peripheral immune cell dynamics. Our analysis revealed that successful reperfusion significantly elevates regulatory T cell (Treg) proportions compared to non-reperfused controls. Across experimental groups, higher interleukin-10 (IL-10) levels generally accompanied greater Treg abundance and better motor performance. Targeted intra-arterial delivery of IL-10 at the exact time of reperfusion directly attenuated cerebral injury and improved neurological outcomes. These findings suggest that amplifying anti-inflammatory signaling post-reperfusion may provide neuroprotection, positioning intra-arterial IL-10 as a potential adjunctive neurotherapeutic strategy to enhance the efficacy of mechanical thrombectomy.