论文部分内容阅读
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 ofREV-ERBα agonist GSK41 12 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factorkappa B (NF-KB) pathway.In BV2 cells,pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-κBalpha (IκBα) kinase (IκK),thus restraining the phosphorylation and degradation of IκBα,and blocked the nuclear translocation ofp65,a NF-KB 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.