Microglial immunosurveillance after ischemic stroke: dynamic phenotypes, neurovascular interactions, and therapeutic opportunities
TL;DR
Therapeutic strategies should seek to redirect specific microglial programs rather than broadly suppress neuroinflammation, and potential approaches include modulating inflammasome and complement signaling, oxidative stress, phagocytosis, lipid metabolism, and repair-associated trophic functions.
Abstract
Ischemic stroke induces complex neuroimmune responses that extend beyond acute neuronal injury and involve dynamic interactions among microglia, the neurovascular unit, and peripheral immune cells. Microglia rapidly transition from homeostatic surveillance to damage sensing, cytokine production, phagocytic clearance, and tissue remodeling. Their functions are highly context-dependent: early microglial responses may promote blood–brain barrier protection, debris clearance, and tissue repair, whereas excessive or persistent activation may exacerbate oxidative stress, inflammasome signaling, complement-mediated synaptic pruning, white matter injury, and chronic peri-infarct inflammation. Recent single-cell studies have challenged the traditional M1/M2 framework by identifying multiple transcriptional states that vary across disease stages, brain regions, and systemic immune conditions. Following stroke, microglia interact closely with endothelial cells, pericytes, astrocytes, infiltrating macrophages, neutrophils, lymphocytes, and platelets, thereby linking local neuroinflammation with systemic immunosuppression and infection risk. Therapeutic strategies should therefore seek to redirect specific microglial programs rather than broadly suppress neuroinflammation. Potential approaches include modulating inflammasome and complement signaling, oxidative stress, phagocytosis, lipid metabolism, and repair-associated trophic functions. Clinical translation remains limited by narrow therapeutic windows, patient heterogeneity, difficulty distinguishing resident microglia from infiltrating macrophages, and the absence of validated clinical biomarkers. Future research should integrate longitudinal microglial profiling, neurovascular biology, systemic immune monitoring, and functional recovery measures to develop interventions tailored to specific stages of stroke recovery.