How IL-9 signaling Influences Astrocytes and ultimately Contributes to BBB Disruption after Ischemic Stroke

Abstract

Despite the improvement of reperfusion therapies, acute ischemic stroke is still one of the main causes of death and long-term disability. Recovery is restricted by secondary neuronal injury, which is caused by neuroinflammation, edema and blood brain barrier (BBB) disruption. In this study, the PubMed and Google Scholar databases were searched for the following terms: “IL‑9,” “astrocytes,” “BBB,” and “ischemic stroke.” The retrieved experimental studies and evidence-based syntheses (2016–2026) were performed and a narrative review was conducted. There is evidence that BBB breakdown occurs early (hours) as well as later through processes initiated by proteases/cytokines involving endothelial dysfunction, oxidative stress, ATP depletion, increased caveolae mediated transcytosis, and loss of tight-junction proteins (claudin‑5, occludin) through VEGF‑A/VEGFR2 signaling, eNOS activation and MMP‑9–mediated degradation. Increased levels of IL-9 are found during stroke, astrocytes express receptors to IL-9 and IL-9 activated JAK/STAT3 signaling can promote reactive astrogliosis and astrocyte-derived VEGF-A (and possibly MMP-9), which further increases vascular permeability and BBB disruption. Experimental therapies that target IL‑9 or downstream targets (STAT3, VEGF‑A/VEGFR2, PLCγ–eNOS, MMP‑9) have the effect of reducing VEGF‑A, preserving tight junctions, and limiting damage to the BBB; GLP‑1 receptor agonists (e.g., exenatide/Ex‑4) have been found to inhibit inflammatory outputs of astrocytes without impairing beneficial microglial functions. These results identify and validate an underexplored therapeutic opportunity, the IL-9–astrocyte–VEGF‑A axis, and point to multi-target, time- and cell-type-specific therapeutic approaches using biomarkers (such as MMP-9 levels, polymorphisms). Heterogeneity of the studies and publication bias reduces the translational potential and standardized longitudinal experimental and clinical validation is required.