1. Academic Validation
  2. Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway

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

  • Acta Pharmacol Sin. 2019 Jan;40(1):26-34. 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 2
Affiliations

Affiliations

  • 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.
  • 2 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. [email protected].
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16988
    98.97%, REV-ERBα/β Agonist