Neuroinflammation after stroke: initiation, amplification and therapeutic prospects

Stroke is one of the leading causes of death and long-term disability worldwide, placing a significant health and economic burden on society. Despite significant advancements in acute reperfusion therapy, the narrow treatment window makes it challenging for many patients to get the help they need. The pathophysiological core of post-stroke brain injury lies in the cascade of neuroinflammation amplification initiated by the activation of innate immune cells that release a variety of inflammatory mediators, forming a positive feedback loop that keeps amplifying inflammatory signals. This uncontrolled and self-sustaining excessive inflammation, a major driver of secondary neuronal injury, also contributes to neurological deficits. Therefore, it is crucial to understand how neuroinflammation is initiated. This review aims to systematically elucidate the initiation mechanisms and cascade amplification effects of neuroinflammation after stroke, revealing how glial cell metabolic reprogramming triggered by damage-associated molecular patterns (DAMPs) drives blood-brain barrier (BBB) disruption and peripheral immune cell infiltration. It also focuses on the interactive crosstalk between inflammation and various cell death pathways, analyzing the molecular mechanisms that form a vicious cycle and exacerbate secondary brain injury. Furthermore, by reviewing existing intervention strategies targeting neuroinflammation, this paper discusses clinical translation barriers such as patient heterogeneity and drug delivery efficiency, with the goal of providing a theoretical foundation and strategic reference for the precise intervention of post-stroke neuroinflammation. In the future, as single-cell sequencing and multi-omics analysis techniques become more widely available, researchers will be able to more systematically clarify the spatiotemporal dynamics and individual heterogeneity of neuroinflammation mechanisms. The findings included in this review could make a difference in moving relevant basic research into clinical applications and offer important insights for developing new, precise and effective targeted treatments.