Abstract A017: Intra-Arterial IL-6 Activates Microglia-Driven VEGF Repair to Improve Stroke Recovery

Even after successful reperfusion, most stroke patients remain disabled, highlighting the urgent need for therapies that promote true repair. Angiogenesis is a critical yet underexploited process in recovery. Here we report the first demonstration of a monocyte–interleukin-6 (IL-6)–microglia axis that induces a pro-angiogenic microglial switch and drives VEGF-mediated repair. We define this pathway in a mouse stroke model, confirm repair-associated microglia (RAMs) in human tissue, validate it in an ex vivo ischemia model, and extend these findings to an endovascular therapy that reduced stroke volume, enhanced angiogenesis, and improved recovery in vivo. In a transient middle cerebral artery occlusion (MCAo) model, VEGF+ RAMs emerged during the subacute phase (days 3–7). Flow cytometry and histology showed this transition required infiltrating CCR2+ monocytes. CCR2 deletion blocked the VEGF switch, reduced peri-infarct microvascular density by 44.7% ± 6.3 (p<0.01), and increased infarct size by 34.8% ± 5.5 (p<0.01). Imaging confirmed VEGF localization to peri-infarct regions. Reconstitution with wild-type, but not IL-6–deficient, bone marrow–derived myeloid cells restored VEGF+ microglia, increased microvascular density by 2.1-fold ± 0.4 (p<0.01), and improved modified neurological severity scores (mNSS) by 41.2% ± 7.0 (p<0.01), establishing IL-6 as a necessary signal. To establish clinical relevance, VEGF+ RAMs were observed in post-stroke cortical specimens, enriched around neovessels (Figure 1). In ex vivo human cortical slices subjected to 1 h of ischemia, IL-6 treatment or monocyte co-culture increased VEGF expression in microglia by 3.2-fold ± 0.6 (p<0.01) compared with controls, confirming conservation of this pathway in patients. To translate these findings, intra-arterial IL-6 delivery immediately post-MCAo, simulating thrombectomy, enhanced VEGF+ RAMs, increased microvascular density by 59.6% ± 8.1 (p<0.001), reduced infarct volume by 29.7% ± 6.8 (p<0.01), and improved mNSS recovery (46.3% ± 5.9, p<0.001) compared with controls or intravenous delivery. Together, these results identify the monocyte–microglia–IL-6 axis as a central driver of VEGF-mediated repair. Intra-arterial IL-6 during thrombectomy may enable the first repair-focused stroke therapy, designed to both limit injury and accelerate recovery.