Sestrin2 (SESN2) is a stress-inducible protein and acts as a neuroprotective regulator. The present study aimed to explore the antidepressant activity of SESN2 and its relevant mechanism. Depression mouse model was established by chronic unpredictable mild stress (CUMS) for a successive 5 weeks. Behaviors tests were conducted to examine depressive-like behaviors including sugar preference test, tail suspension test and open field test. The expression of SESN2 and ferroptosis-related proteins was examined by western blot. The production of cytokines was measured by ELISA. Iron deposition was assessed using Prussian blue staining and Fe2+ content was measured using commercial kits. Lipid peroxidation was evaluated by thiobarbituric acid reactive substances assay. BV-2 cells were treated with LPS to induce microglial activation, which was evaluated by the iba-1 level adopting immunofluorescence assay. The ferroptosis inducer Erastin was adopted for the pretreatment in BV-2 cells to conduct a rescue experiment. SESN2 was downregulated in CUMS-induced mice, and SESN2 overexpression dramatically ameliorated CUMS-induced depression-like behaviors. Meanwhile, SESN2 reduced the production of pro-inflammatory cytokines and iba-1 level in hippocampus of CUMS mice, as well as reducing iron deposition and lipid peroxidation, demonstrating that SESN2 reduced microglial activation, neuroinflammation and ferroptosis in CUMS mice. Similarly, SESN2 also restricted iba-1 level, pro-inflammatory cytokines production, and ferroptosis in LPS-induced BV-2 cells, which was partly reversed by additional treatment of Erastin. These findings suggest that SESN2 possesses potent antidepressant property through inhibiting ferroptosis and neuroinflammation.

中文翻译：

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Sestrin2 通过抑制铁死亡来减轻 CUMS 小鼠的抑郁样行为和神经炎症。

Sestrin2 (SESN2) 是一种应激诱导蛋白，可作为神经保护调节剂。本研究旨在探讨SESN2的抗抑郁活性及其相关机制。采用连续5周的慢性不可预测轻度应激(CUMS)建立抑郁小鼠模型。进行行为测试来检查抑郁样行为，包括糖偏好测试、悬尾测试和旷场测试。通过蛋白质印迹检查SESN2和铁死亡相关蛋白的表达。通过ELISA测量细胞因子的产生。使用普鲁士蓝染色评估铁沉积，并使用商业试剂盒测量 Fe2+ 含量。通过硫代巴比妥酸反应物质测定评估脂质过氧化。用LPS处理BV-2细胞诱导小胶质细胞活化，采用免疫荧光法检测iba-1水平。采用铁死亡诱导剂Erastin对BV-2细胞进行预处理，进行拯救实验。 SESN2 在 CUMS 诱导的小鼠中下调，SESN2 过度表达显着改善 CUMS 诱导的抑郁样行为。同时，SESN2减少了CUMS小鼠海马促炎细胞因子的产生和iba-1水平，并减少了铁沉积和脂质过氧化，表明SESN2减少了CUMS小鼠的小胶质细胞活化、神经炎症和铁死亡。同样，SESN2 还限制了 LPS 诱导的 BV-2 细胞中的 iba-1 水平、促炎细胞因子的产生和铁死亡，而 Erastin 的额外治疗可部分逆转这种情况。这些发现表明 SESN2 通过抑制铁死亡和神经炎症而具有有效的抗抑郁特性。