Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown. Adult male C57BL/6 mice (N = 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2. Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (p < 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization. Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux. Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.

中文翻译：

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Sestrin2 通过 mTOR 介导的自噬通量调节小胶质细胞极化以减轻实验性脑缺血期间的炎症

神经炎症是脑缺血的主要发病机制。小胶质细胞被激活并极化为促炎 M1 表型或抗炎 M2 表型，它们是神经炎症的关键介质。Sestrin2 具有抗缺血性脑损伤的促生存特性。然而，sestrin2是否具有通过改变小胶质细胞极化的抗炎功能及其潜在机制尚不清楚。成年雄性 C57BL/6 小鼠 (N = 108) 经历短暂的大脑中动脉闭塞 (tMCAO) 并用外源性 sestrin2 治疗。确定神经功能缺损评分和梗塞体积。通过TUNEL染色和Western印迹检查细胞凋亡。炎症介质、M1/M2 特异性标志物的表达，通过逆转录聚合酶链反应、免疫染色和蛋白质印迹检测信号通路。为了探索潜在机制，对原代神经元进行氧-葡萄糖剥夺 (OGD)，然后用与不同剂量 sestrin2 孵育的 BV2 细胞的含氧条件培养基处理。与对照组相比，Sestrin2 在 tMCAO 后减轻了神经功能缺损、梗死体积和细胞凋亡（p < 0.05）。Sestrin2具有抗炎作用，可以抑制M1小胶质细胞极化，促进M2小胶质细胞极化。来自与 sestrin2 一起培养的 BV2 细胞的条件培养基可减少体外 OGD 后的神经元凋亡。此外，我们证明了 sestrin2 通过抑制哺乳动物雷帕霉素靶蛋白 (mTOR) 信号通路和恢复自噬通量，将小胶质细胞驱动至 M2 表型。Sestrin2 通过在缺血性小鼠脑中将小胶质细胞极化从 M1 表型转变为 M2 表型表现出神经保护作用，这可能是由于 mTOR 信号通路的抑制和自噬通量的恢复。