Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis.
Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis.
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DOI：
10.1186/s12974-020-02040-8
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发表时间：
2021-01-05
影响因子：
9.3
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Li Y;Song W;Tong Y;Zhang X;Zhao J;Gao X;Yong J;Wang H
NLRP3介导的上睑下垂受miRNA-27A调控，在抑郁症的发生发展中起关键作用。异甘草素是一种酚类黄酮类化合物，已被证明能抑制NLRP3介导的下垂。然而，目前尚不清楚异甘草素是否通过刺激miRNA-27A而降低NLRP3介导的下垂，从而发挥抗抑郁作用。因此，在本研究中，我们探索了异甘草素的抗抑郁活性及其可能的机制。采用定量逆转录聚合酶链式反应(qRT-PCR)检测抑郁患者或小鼠的miRNA-27A的表达。荧光素酶报告分析表明miRNA-27A与SYK之间的联系。建立脂多糖(LPS)和慢性社会失败应激(CSDS)抑郁模型，观察异甘草素的抗抑郁作用。此外，还观察了MIRNA-27A/SYK/NF-κB轴和NLRP3介导的下垂的变化。通过使用miRNA-27A抑制剂和miRNA-27A的模拟物，进一步研究了miRNA-27A在异甘草素相关抗抑郁作用中的作用。结果表明，抑郁症患者血清中miRNA-27A表达下调，抑郁模型大鼠血清和海马区miRNA-27A表达降低。MiRNA-27A模拟孵育显著降低了SYK基因的表达。Isoliquiritin可显著减轻内毒素或CSDS诱导的抑郁症状，以及CSDS诱导的焦虑行为。在海马区，脂多糖和柴胡多糖组miRNA-27AmRNA表达降低，Syk、p-NF-κB和NLRP3蛋白水平升高：裂解Caspase-1、IL-1β和GSDMD-N；升高IL-1β、IL-6和α浓度，这些均可被异甘草素恢复。同时，异甘草素上调大鼠海马神经元NeuN蛋白水平，改善神经元存活和形态，减少下垂相关神经细胞死亡。此外，异甘草素对脂多糖和三磷酸腺苷诱导的NLRP3炎性小体激活有保护作用，表现为p-NF-κB、NLRP3蛋白水平降低，Caspase-1、IL-1β和GSDMD-N蛋白水平降低，miRNA-27AmRNA表达上调，SYKmRNA和蛋白水平降低。然而，miRNA-27A抑制剂显著逆转了异甘草素在CSDS小鼠体内和体外产生的治疗效果。此外，异甘草素对脂多糖和三磷酸腺苷处理的原代小胶质细胞的保护作用与miRNA-27A类似物相似。综上所述，这些发现表明异甘草素具有强大的抗抑郁作用，这需要miRNA-27A/SYK/NF-κB轴通过NLRP3级联途径控制下垂的降低。网上版载有补充材料，可在10.1186/s12974-020-02040-8查阅。
The NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism. Expression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-κB axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a. Our results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-κB, and NLRP3: cleaved Caspase-1, IL-1β, and GSDMD-N: and elevated the concentration of IL-1β, IL-6, and TNF-α, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-κB, NLRP3; cleaved Caspase-1, IL-1β, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-κB axis controlled decrease of pyroptosis via NLRP3 cascade. The online version contains supplementary material available at 10.1186/s12974-020-02040-8.
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影响因子：
4.6
作者：
Ismael S;Zhao L;Nasoohi S;Ishrat T
通讯作者：
Ishrat T
影响因子：
7.3
作者：
de Castro RJA;Siqueira IM;Jerônimo MS;Basso AMM;Veloso Junior PHH;Magalhães KG;Leonhardt LC;de Oliveira SAM;Bürgel PH;Tavares AH;Bocca AL
通讯作者：
Bocca AL
DOI：
10.4314/ajtcam.v11i2.18
发表时间：
2014-01-01
影响因子：
--
作者：
Shi, Xiaoli;Zou, Ming;Li, Xu
通讯作者：
Li, Xu
DOI：
10.1016/j.bbi.2018.06.010
发表时间：
2018-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Herman FJ;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
4.3
作者：
Ju, MinJie;Liu, BoFei;Luo, Zhe
通讯作者：
Luo, Zhe