Pan Zhenguo, Yu Xiaoyu, Wang Weiwei, Shen Kai, Chen Jianwei, Zhang Yunfeng, Huang Rongrong
Stroke Center and Department of Neurology, Department of Pharmacy, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Department of Neurology, People's Hospital of Xiangshui County, Yancheng, China.
J Neurochem. 2024 Sep;168(9):2640-2653. doi: 10.1111/jnc.16126. Epub 2024 May 17.
Most central nervous diseases are accompanied by astrocyte activation. Autophagy, an important pathway for cells to protect themselves and maintain homeostasis, is widely involved in regulation of astrocyte activation. Reactive astrocytes may play a protective or harmful role in different diseases due to different phenotypes of astrocytes. It is an urgent task to clarify the formation mechanisms of inflammatory astrocyte phenotype, A1 astrocytes. Sestrin2 is a highly conserved protein that can be induced under a variety of stress conditions as a potential protective role in oxidative damage process. However, whether Sestrin2 can affect autophagy and involve in A1 astrocyte conversion is still uncovered. In this study, we reported that Sestrin2 and autophagy were significantly induced in mouse hippocampus after multiple intraperitoneal injections of lipopolysaccharide, with the elevation of A1 astrocyte conversion and inflammatory mediators. Knockdown Sestrin2 in C8-D1A astrocytes promoted the levels of A1 astrocyte marker C3 mRNA and inflammatory factors, which was rescued by autophagy inducer rapamycin. Overexpression of Sestrin2 in C8-D1A astrocytes attenuated A1 astrocyte conversion and reduced inflammatory factor levels via abundant autophagy. Moreover, Sestrin2 overexpression improved mitochondrial structure and morphology. These results suggest that Sestrin2 can suppress neuroinflammation by inhibiting A1 astrocyte conversion via autophagy, which is a potential drug target for treating neuroinflammation.
大多数中枢神经疾病都伴有星形胶质细胞激活。自噬作为细胞自我保护和维持内稳态的重要途径，广泛参与星形胶质细胞激活的调控。由于星形胶质细胞的不同表型，反应性星形胶质细胞在不同疾病中可能发挥保护或有害作用。阐明炎症性星形胶质细胞表型（A1星形胶质细胞）的形成机制是一项紧迫任务。Sestrin2是一种高度保守的蛋白质，在多种应激条件下可被诱导，在氧化损伤过程中发挥潜在保护作用。然而，Sestrin2是否能影响自噬并参与A1星形胶质细胞转化仍不清楚。在本研究中，我们报道多次腹腔注射脂多糖后，小鼠海马中Sestrin2和自噬显著被诱导，同时A1星形胶质细胞转化及炎症介质水平升高。敲低C8-D1A星形胶质细胞中的Sestrin2可促进A1星形胶质细胞标志物C3 mRNA和炎症因子水平升高，而自噬诱导剂雷帕霉素可使其恢复。在C8-D1A星形胶质细胞中过表达Sestrin2可通过丰富的自噬减弱A1星形胶质细胞转化并降低炎症因子水平。此外，Sestrin2过表达改善了线粒体结构和形态。这些结果表明，Sestrin2可通过自噬抑制A1星形胶质细胞转化来抑制神经炎症，这是治疗神经炎症的一个潜在药物靶点。
