Abstract
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.
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Acknowledgements
This work was supported by the National Key Scientific R&D Program of China (No. 2016YFC1306000), the National Natural Science Foundation of China (No's. 31471012, 81761148024, and 31330030), Suzhou Clinical Research Center of Neurological Disease (No. Szzx201503) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
Author contribution
Dong-kai Guo performed most of the experiments and analyzed the data as well as drafted and revised manuscript; Yao Zhu supplemented experiments and revised the manuscript; Hong-yang Sun performed animal experiments; Xing-yun Xu performed immunoblot assays; Shun Zhang performed immunoblot assays; Zong-bing Hao performed immunoblot assays; Guang-hui Wang revised the manuscript; Chen-chen Mu performed immunoblot analyses; Hai-gang Ren analyzed the data, drafted the manuscript, and discussed the experiments.
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Guo, Dk., Zhu, Y., Sun, Hy. et al. Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway. Acta Pharmacol Sin 40, 26–34 (2019). https://doi.org/10.1038/s41401-018-0064-0
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DOI: https://doi.org/10.1038/s41401-018-0064-0
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