Pharmacological activation of REV-ERBα represses LPSinduced microglial activation through the NF-κB pathway

Authors: Dong-kai Guo1, Yao Zhu1, Hong-yang Sun1, Xing-yun Xu1, Shun Zhang1, Zong-bing Hao1, Guang-hui Wang1, Chen-chen Mu1, Hai-gang Ren1
1 Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Correspondence to: Hai-gang Ren:,
DOI: 10.1038/s41401-018-0064-0
Received: 31 January 2018
Accepted: 5 June 2018
Advance online: 27 June 2018


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.
Keywords: REV-ERBα; GSK4112; SR9011; LPS; microglia; neuroinflammation; NF-κB

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