The NETs-cGAS-STING Axis in Ischemic Stroke: Linking Neutrophil-Microglia Crosstalk, Immunothrombosis, and Neuroinflammation.

The immune and inflammatory responses following ischemic stroke involve aberrant DNA exposure, immunothrombosis, and innate immune activation. Post-stroke, damage-associated DNA signals from multiple sources may activate DNA-sensing pathways; however, how DNA from distinct sources links peripheral immune activation with inflammatory amplification within the brain remains incompletely understood. Among these, neutrophil extracellular traps (NETs), as DNA-rich extracellular structures, may represent a potential link connecting vascular inflammation, immunothrombosis, and intracerebral DNA sensing. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a key DNA-sensing axis, mediates distinct inflammatory and stress responses across various stroke-associated cell types. This review summarizes the mechanisms of DNA recognition, NET-mediated immunothrombosis, and neuroinflammatory damage, as well as the functional characteristics of cGAS-STING signaling in different cell types. Based on current evidence, we propose a potential NETs-cGAS-STING inflammatory amplification framework: NET-derived DNA may contribute to DNA-sensing activation within the ischemic brain and promote microglial inflammatory responses, while the resulting inflammatory factors and chemotactic signals may further promote neutrophil recruitment and secondary NET formation, thereby potentially creating a feed-forward loop linking peripheral immune activation with neuroinflammation. We further discuss the spatiotemporal heterogeneity of this axis, therapeutic targets, and challenges for clinical translation. Overall, the NETs-cGAS-STING framework provides an integrated conceptual perspective for understanding the intercellular interactions underlying DNA recognition and the sustained amplification of inflammation following stroke, and offers insights into future precision immune interventions tailored to disease stage, lesion characteristics, and cell-specific responses.