Endothelial STING promotes NET-associated thromboinflammation via the MYH9–P-selectin axis after traumatic brain injury

Traumatic brain injury (TBI) induces secondary injury, including thromboinflammatory responses within the cerebral microvasculature, which contribute to blood–brain barrier (BBB) disruption and impaired microcirculatory function. However, the endothelial mechanisms driving this process remain poorly understood. Here, we identify endothelial stimulator of interferon genes (STING) as a regulator of post-traumatic cerebrovascular thromboinflammation. Single-cell RNA sequencing and human TBI tissue analysis revealed endothelial STING upregulation associated with an inflammatory endothelial phenotype and neutrophil adhesion. In a controlled cortical impact murine model, TBI triggered neutrophil adhesion, neutrophil extracellular trap (NET) formation, platelet activation, and fibrin deposition, leading to BBB disruption and impaired cortical microcirculation. Global STING deficiency attenuated TBI-induced platelet activation, whereas both global STING deficiency and cerebrovascular endothelial-specific STING knockdown reduced NET-associated thromboinflammation, preserved BBB integrity, and improved cortical perfusion. Mechanistically, endothelial STING interacted with MYH9 and promoted MYH9-dependent P-selectin mobilization and release, thereby enhancing endothelial–neutrophil interaction and NET formation. Notably, STING-driven NET induction was mainly dependent on P-selectin rather than canonical type I interferon signaling. Pharmacological blockade of P-selectin or inhibition of MYH9 mitigated cerebrovascular thromboinflammation, reduced BBB disruption and cerebral hypoperfusion, and improved functional outcomes after TBI. Together, these findings identify the endothelial STING–MYH9–P-selectin axis as a driver of post-traumatic cerebrovascular injury and a potential therapeutic target for limiting secondary brain damage after TBI.