Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy.
Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy.
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槲皮素通过 NLRP3 炎性体和线粒体自噬之间的相互作用阻碍小胶质细胞激活以减轻神经毒性
DOI：
10.1016/j.redox.2021.102010
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发表时间：
2021-08
期刊：
影响因子：
11.4
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Han X;Xu T;Fang Q;Zhang H;Yue L;Hu G;Sun L
活化的小胶质细胞是大脑中一种重要的先天免疫细胞，它们向细胞外环境分泌炎性细胞因子，对周围神经元施加神经毒性，并参与许多脑部疾病的发病机制。槲皮素是一种天然的类黄酮，具有抗炎和抗氧化的特性。已有研究表明，活性氧（ROS）应激的增加和自噬的减少都参与了小胶质细胞的激活。在本研究中，我们发现曲能显著减弱lps诱导的炎症因子产生、细胞增殖和NF-κB活化。重要的是，Qu降低了NLR家族，pyrin结构域含有三种（NLRP3）炎症小体和热降解相关蛋白的水平，包括NLRP3，活性caspase-1， GSDMD n端和裂解的IL-1β。进一步研究表明，曲的这种抗炎作用与线粒体自噬调节有关。重要的是，曲促进线粒体自噬，增强受损线粒体的消除，从而减少mtROS积累，减轻NLRP3炎性体的激活。然后，我们证实了Qu治疗可以保护原代神经元免受lps诱导的小胶质细胞毒性，并减轻抑郁症和PD小鼠模型的神经变性。进一步给药IL-1β使曲在体内和体外的神经保护作用减弱。本研究表明，曲通过促进线粒体自噬，抑制mtros介导的小胶质细胞NLRP3炎性体的激活，从而预防神经元损伤，这为神经炎症相关疾病的治疗提供了一种潜在的新策略。
Activated microglia are an important type of innate immune cell in the brain, and they secrete inflammatory cytokines into the extracellular milieu, exert neurotoxicity to surrounding neurons and are involved in the pathogenesis of many brain disorders. Quercetin (Qu), a natural flavonoid, is known to have anti-inflammatory and antioxidant properties. Previous studies have shown that both increased reactive oxygen species (ROS) stress and decreased autophagy participate in the activation of microglial. In the current study, we showed that Qu significantly attenuated LPS-induced inflammatory factor production, cell proliferation and NF-κB activation of microglia. Importantly, Qu decreased the levels of NLR family, pyrin domain containing three (NLRP3) inflammasome and pyroptosis-related proteins, including NLRP3, active caspase-1, GSDMD N-terminus and cleaved IL-1β. Further study indicated that this anti-inflammatory effect of Qu was associated with mitophagy regulation. Importantly, Qu promoted mitophagy to enhance damaged mitochondrial elimination, which then reduced mtROS accumulation and alleviated NLRP3 inflammasome activation. Then, we confirmed that Qu treatment protected primary neurons against LPS-induced microglial toxicity and alleviated neurodegeneration in both depression and PD mouse models. Further IL-1β administration blunted these neuroprotective effects of Qu in vitro and in vivo. This work illustrated that Qu prevents neuronal injury via inhibition of mtROS-mediated NLRP3 inflammasome activation in microglia through promoting mitophagy, which provides a potential novel therapeutic strategy for neuroinflammation-related diseases.
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