Fig. 3

Elevated levels of NETs were observed in both brain tissue and peripheral blood samples obtained from tMCAO model animals and stroke patients. The formation of NETs is believed to be influenced by various factors, including HMGB1, PKM2, s100A8/A9, and ATP. HMGB1, a nonhistone protein, is induced by platelet activation and interacts with DNA to facilitate the release of NETs. PKM2, a subtype of pyruvate kinase, promotes the expression of neutrophil inflammatory factors and increases the production of NETs. ATP serves as an activator of P2X7R in neutrophils, thereby initiating NETosis through the generation of ROS. Additionally, s100A8/A9 selectively targets Toll-like receptors, leading to platelet pyroptosis, which subsequently facilitates the formation of NETs. Consequently, the integrity of the blood–brain barrier is compromised, neovascularization is impeded, and vascular damage ensues, accompanied by nerve impairment resulting in diminished limb functionality. Nonetheless, the detrimental consequences of these lesions can be alleviated by inhibiting NETs with Ly6G, PAD4 inhibitors, and DNase1