异甘草苷通过 miRNA-27a/SYK/NF-κB 轴抑制 NLRP3 介导的细胞焦亡改善抑郁症,Journal of Neuroinflammation

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异甘草苷通过 miRNA-27a/SYK/NF-κB 轴抑制 NLRP3 介导的细胞焦亡改善抑郁症
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2021-01-05 , DOI: 10.1186/s12974-020-02040-8
Yuanjie Li ₁ , Wen Song ₁ , Yue Tong ₁ , Xia Zhang ₁ , Jianjun Zhao ₁ , Xiaojuan Gao ₁ , Jingjiao Yong ₁ , Hanqing Wang _{1,

2,

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Affiliation

可由 miRNA-27a 调节的 NLRP3 介导的细胞焦亡是抑郁症发展的关键参与者。异甘草苷是一种酚类黄酮化合物，已被证明可以抑制 NLRP3 介导的细胞焦亡。然而，异甘草苷是否可以通过刺激 miRNA-27a 来降低 NLRP3 介导的细胞焦亡，从而赋予抗抑郁活性仍然未知。因此，在目前的研究中，我们探索了异甘草苷的抗抑郁活性及其潜在机制。使用 qRT-PCR 测量抑郁症患者或小鼠中 miRNA-27a 的表达。进行荧光素酶报告基因检测以说明 miRNA-27a 和 SYK 之间的联系。建立脂多糖 (LPS) 和慢性社会失败应激 (CSDS) 抑郁模型以研究异甘草苷的抗抑郁作用。还检查了 miRNA-27a/SYK/NF-κB 轴和 NLRP3 介导的细胞焦亡的变化。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。我们的研究结果表明，在抑郁症患者的血清中 miRNA-27a 表达下调，并且在抑郁症啮齿动物模型中观察到 miRNA-27a 的血清和海马表达降低。miRNA-27a 模拟物孵育显着降低了 SYK 基因表达。异甘草苷显着减轻 LPS 或 CSDS 诱导的抑郁症状，以及 CSDS 诱导的焦虑行为。在海马中，LPS 和 CSDS 降低了 miRNA-27a mRNA 的表达；增加 SYK、p-NF-κB 和 NLRP3 的蛋白质水平：裂解 Caspase-1、IL-1β 和 GSDMD-N：并提高 IL-1β、IL-6 和 TNF-α 的浓度，均通过异甘草苷给药恢复。同时，异甘草苷上调海马 NeuN 蛋白水平，改善神经元的存活和形态，并减少与细胞焦亡相关的神经元细胞死亡。此外，异甘草素可保护初级小胶质细胞免受 LPS 的侵害，三磷酸腺苷 (ATP) 在体外引发 NLRP3 炎性体激活，p-NF-κB、NLRP3 的蛋白质水平下降证明了这一点；裂解的 Caspase-1、IL-1β 和 GSDMD-N；上调 miRNA-27a mRNA 表达；并降低 SYK 的 mRNA 和蛋白质水平。然而，miRNA-27a 抑制剂在 CSDS 小鼠和体外显着逆转了异甘草苷产生的治疗效果。此外，异甘草苷的细胞保护作用与 LPS 和 ATP 处理的原代小胶质细胞中的 miRNA-27a 模拟物相似。综合起来，

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Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis

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.

更新日期：2021-01-05

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