Microglia-driven neuroinflammation in ischemic stroke: insights from high altitude hypoxia.

Microglia are key regulators of neuroinflammation and neuronal survival after ischemic stroke. Emerging single-cell, transcriptomic, and metabolic studies show that ischemia induces rapid microglial reprogramming toward pro-inflammatory states that exacerbate neuronal death, oxidative stress, blood-brain barrier (BBB) disruption, and white-matter injury. Multiple pathways, including TLR4/NF-κB, NLRP3 inflammasome activation, Notch1-JAK/STAT signaling, epigenetic modulators such as HDAC3 and METTL14, and metabolic shifts involving AMPK/mTOR/HIF1α, collectively shape post-stroke microglial polarization. High-altitude hypoxia elicits similar inflammatory responses, activating microglia through RAGE-MAPK/NFκB signaling, CX3CL1/CX3CR1-dependent synaptic pruning, mitochondrial dysfunction, and lactate-mediated chromatin changes, highlighting hypoxia as a convergent driver of neuroinflammation. Modulating microglial activity, therefore, represents a promising therapeutic strategy. A wide range of natural compounds (e.g., curcumin, acteoside, astagaloside IV, artemisinin), synthetic agents (e.g., DBZ, resolvin D1), and cellular/molecular cellular interventions (e.g., rhFGF21, S100A9 inhibition, RBM3 induction) have shown efficacy in reducing inflammation, preserving BBB integrity, improving mitochondrial function, and promoting M2-like reparative phenotypes in preclinical models. Advances in understanding microglial subtypes, including CH25H+, OASL+, CD11c+, and antioxidant Prdx1-enriched populations, further highlight their dynamic roles across injury and repair. This review presents current insights into microglial signalling, epigenetic and metabolic regulation, and therapeutic targeting in ischemic stroke, integrating parallel insights from high-altitude hypoxia. Together, these prospectives illuminate microglia as crucial mediators of neurovascular injury and recovery, and highlight opportunities for translating microglia-directed therapies into clinical interventions.