Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression.
Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression.
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星形胶质细胞中NLRP3炎症小体的解偶联蛋白2调节及其对抑郁症的影响
DOI：
10.1016/j.redox.2016.08.006
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发表时间：
2016-10
期刊：
影响因子：
11.4
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Du, Ren-Hong;Wu, Fang-Fang;Lu, Ming;Shu, Xiao-dong;Ding, Jian-Hua;Wu, Guangyu;Hu, Gang
线粒体解偶联蛋白2（UCP 2）被认为是控制活性氧（ROS）产生的重要分子，而星形胶质细胞是负责ROS产生和脑内炎症反应的主要细胞。然而，UCP 2在星形胶质细胞中的功能以及星形胶质细胞UCP 2对抑郁症的贡献仍然不确定。在此，我们证明了UCP 2基因敲除（KO）小鼠在慢性轻度应激（CMS）诱导的抑郁症快感缺失模型中表现出加重的抑郁样行为、受损的神经发生和增强的星形胶质细胞损失。我们进一步发现，UCP 2消融显著增强了海马和星形胶质细胞中炎症样受体蛋白3（NLRP 3）的激活。UCP 2缺陷促进星形胶质细胞线粒体损伤、ROS产生以及硫氧还蛋白相互作用蛋白（TXNIP）与NLRP 3的物理结合。此外，瞬时表达外源性UCP 2部分挽救了UCP 2消融对星形胶质细胞的有害影响。这些数据表明，UCP 2负调节NLRP 3炎性体的活化，并抑制星形胶质细胞中的ROS-TXNIP-NLRP 3通路。总的来说，我们的研究结果表明，UCP 2调节星形胶质细胞的炎症反应，并在抑郁症的发病机制中发挥重要作用，UCP 2可能是一个有前途的治疗抑郁症的目标。UCP 2基因敲除可加重小鼠的抑郁行为UCP 2基因敲除可增强CMS对神经发生的抑制作用。UCP 2缺失增强海马和星形胶质细胞中的NLRP 3炎性体活化。UCP 2抑制ROS-TXNIP-NLRP 3信号传导。
Mitochondrial uncoupling protein 2 (UCP2) has been well characterized to control the production of reactive oxygen species (ROS) and astrocytes are the major cells responsible for the ROS production and the inflammatory responses in the brain. However, the function of UCP2 in astrocytes and the contribution of astrocytic UCP2 to depression remain undefined. Herein, we demonstrated that UCP2 knockout (KO) mice displayed aggravated depressive-like behaviors, impaired neurogenesis, and enhanced loss of astrocytes in the chronic mild stress (CMS)-induced anhedonia model of depression. We further found that UCP2 ablation significantly enhanced the activation of the nod-like receptor protein 3 (NLRP3) inflammasome in the hippocampus and in astrocytes. Furthermore, UCP2 deficiency promoted the injury of mitochondria, the generation of ROS and the physical association between thioredoxin-interacting protein (TXNIP) and NLRP3 in astrocytes. Moreover, transiently expressing exogenous UCP2 partially rescued the deleterious effects of UCP2 ablation on the astrocytes. These data indicate that UCP2 negatively regulates the activation of NLRP3 inflammasome and inhibited the ROS-TXNIP-NLRP3 pathway in astrocytes. Collectively, our findings reveal that UCP2 regulates inflammation responses in astrocytes and plays an important role in the pathogenesis of depression and that UCP2 may be a promising therapeutic target for depression. UCP2 knockout exacerbates depressive behaviors in mice. UCP2 knockout aggravates CMS-induced the inhibition of neurogenesis. UCP2 deletion enhances NLRP3 inflammasome activation in hippocampus and in astrocyte. UCP2 inhibits the ROS-TXNIP-NLRP3 signaling.
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