Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway.
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.
['Guo|Dong-Kai|DK|', 'Zhu|Yao|Y|', 'Sun|Hong-Yang|HY|', 'Xu|Xing-Yun|XY|', 'Zhang|Shun|S|', 'Hao|Zong-Bing|ZB|', 'Wang|Guang-Hui|GH|', 'Mu|Chen-Chen|CC|', 'Ren|Hai-Gang|HG|']
D000818:Animals D045744:Cell Line, Tumor D005998:Glycine D057809:HEK293 Cells D006801:Humans D007249:Inflammation D008297:Male D008636:Mesencephalon D008810:Mice, Inbred C57BL D017628:Microglia D018696:Neuroprotective Agents D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 D011759:Pyrrolidines D015398:Signal Transduction D013876:Thiophenes D051996:Transcription Factor RelA
REV-ERBα NF-κB neuroinflammation microglia GSK4112 SR9011 LPS