Zhuang Hao, Lei Wen, Wu Qiang, Zhao Songyun, Zhao Yunxuan, Zhang Shizhe, Zhao Ning, Sun Jun, Liu Yuankun
Department of Neurosurgery, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214000, China; Wuxi Medical Center of Nanjing Medical University, Wuxi 214000, China.
Department of Endocrinology, Nanjing Hospital of Traditional Chinese Medicine, Nanjing 210001, China.
Exp Neurol. 2025 Apr;386:115152. doi: 10.1016/j.expneurol.2025.115152. Epub 2025 Jan 18.
Ischemic stroke, resulting from the blockage or narrowing of cerebral vessels, causes brain tissue damage due to ischemia and hypoxia. Although reperfusion therapy is essential to restore blood flow, it may also result in reperfusion injury, causing secondary damage through mechanisms like oxidative stress, inflammation, and excitotoxicity. These effects significantly impact astrocytes, neurons, and endothelial cells, aggravating brain injury and disrupting the blood-brain barrier. CD73, an ectoenzyme that regulates adenosine production through ATP hydrolysis, plays a critical role in purinergic signaling and neuroprotection. During ischemic stroke, CD73 expression is dynamically regulated in response to ischemia and inflammation. It catalyzes the conversion of AMP to adenosine, which activates adenosine receptors to exert neuroprotective effects. Targeting the CD73-adenosine pathway presents a potential therapeutic strategy for mitigating ischemic stroke damage. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes like NLRP3 and caspases, plays a significant role in cerebral ischemia-reperfusion injury. Astrocytes, the most abundant CNS cells, contribute to both neuroprotection and injury, with pyroptosis exacerbating inflammation and brain damage. Regulating astrocyte pyroptosis is a promising therapeutic target. Our study investigates CD73's role in regulating astrocyte pyroptosis during ischemia-reperfusion injury. Using CD73 knockout mice and overexpression models, along with in vitro oxygen-glucose deprivation/reperfusion experiments, we found that CD73 overexpression reduces GSDMD-mediated astrocyte pyroptosis via the A2B/NF-κB pathway. These findings offer a novel approach to reducing neuroinflammation, protecting astrocytes, and improving outcomes in ischemic stroke.
缺血性中风由脑血管阻塞或狭窄引起，会因缺血和缺氧导致脑组织损伤。尽管再灌注治疗对于恢复血流至关重要，但它也可能导致再灌注损伤，通过氧化应激、炎症和兴奋性毒性等机制造成继发性损伤。这些影响对星形胶质细胞、神经元和内皮细胞有显著影响，加重脑损伤并破坏血脑屏障。CD73是一种通过ATP水解调节腺苷生成的胞外酶，在嘌呤能信号传导和神经保护中起关键作用。在缺血性中风期间，CD73的表达会响应缺血和炎症而动态调节。它催化AMP转化为腺苷，腺苷激活腺苷受体发挥神经保护作用。靶向CD73-腺苷途径是减轻缺血性中风损伤的一种潜在治疗策略。焦亡是由NLRP3和半胱天冬酶等炎性小体介导的一种高度炎症性程序性细胞死亡形式，在脑缺血再灌注损伤中起重要作用。星形胶质细胞是中枢神经系统中最丰富的细胞，对神经保护和损伤都有作用，焦亡会加剧炎症和脑损伤。调节星形胶质细胞焦亡是一个有前景的治疗靶点。我们的研究调查了CD73在缺血再灌注损伤期间调节星形胶质细胞焦亡中的作用。使用CD73基因敲除小鼠和过表达模型，以及体外氧糖剥夺/再灌注实验，我们发现CD73过表达通过A2B/NF-κB途径减少GSDMD介导的星形胶质细胞焦亡。这些发现为减少神经炎症、保护星形胶质细胞和改善缺血性中风的预后提供了一种新方法。
