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Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-06-27 , DOI: 10.1038/s41401-018-0064-0
Dong-Kai Guo 1 , Yao Zhu 1 , Hong-Yang Sun 1 , Xing-Yun Xu 1 , Shun Zhang 1 , Zong-Bing Hao 1 , Guang-Hui Wang 1 , Chen-Chen Mu 1 , Hai-Gang Ren 1
Affiliation  

REV-ERBα, the NR1D1 (nuclear receptor subfamily 1, group D, member 1) gene product, is a dominant transcriptional silencer that represses the expression of genes involved in numerous physiological functions, including circadian rhythm, inflammation, and metabolism, and plays a crucial role in maintaining immune functions. Microglia-mediated neuroinflammation is tightly associated with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBα in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacological activation of REV-ERBα affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBα agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-κB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα) kinase (IκK), thus restraining the phosphorylation and degradation of IκBα, and blocked the nuclear translocation of p65, a NF-κB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα). Moreover, REV-ERBα agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBα activity suppresses microglial activation through the NF-κB pathway in the central nervous system.

中文翻译:

REV-ERBα的药理激活可通过NF-κB途径抑制LPS诱导的小胶质细胞激活。

REV-ERBα是NR1D1(核受体亚家族1,D组,成员1)的基因产物,是一种主要的转录沉默子,可抑制涉及许多生理功能(包括昼夜节律,炎症和新陈代谢)的基因的表达,并发挥在维持免疫功能中起关键作用。小胶质细胞介导的神经炎症与各种神经退行性疾病和精神疾病紧密相关。但是,REV-ERBα在神经炎症中的作用尚不清楚。在这项研究中,我们调查了体外和体内REV-ERBα的药理活化是否以及如何影响脂多糖(LPS)诱导的小鼠小胶质细胞的神经炎症。在BV2细胞或原代小鼠培养的小胶质细胞中,REV-ERBα激动剂GSK4112或SR9011的剂量依赖性地通过核因子κB(NF-κB)途径抑制LPS诱导的小胶质细胞活化。在BV2细胞中,用GSK4112预处理可抑制LPS诱导的NF-κBα(IκBα)激酶(IκK)抑制剂的磷酸化,从而抑制IκBα的磷酸化和降解,并阻止NF-κB亚基p65的核易位。从而抑制白细胞介素6(IL-6)和肿瘤坏死因子α(TNFα)等促炎细胞因子的表达和分泌。此外,REV-ERBα激动剂对神经炎症的抑制作用可保护神经元免受小胶质细胞激活引起的损害,这在小鼠腹侧中脑显微注射GSK4112,然后用LPS刺激的小鼠中也得到了证实。
更新日期:2018-06-28
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