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Circadian clock protein Rev-erb? regulates neuroinflammation.

ABSTRACT: Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erb?, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erb?-/- mice. Rev-erb? deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erb?-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-?B signaling. Primary Rev-erb?-/- microglia exhibited proinflammatory phenotypes and increased basal NF-?B activation. Chromatin immunoprecipitation revealed that Rev-erb? physically interacts with the promoter regions of several NF-?B-related genes in primary microglia. Loss of Rev-erb? in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erb?-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erb? deletion influenced neuronal health, as conditioned media from Rev-erb?-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erb?-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erb? as a pharmacologically accessible link between the circadian clock and neuroinflammation.

SUBMITTER: Griffin P

PROVIDER: S-EPMC6421453 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Circadian clock protein Rev-erbα regulates neuroinflammation.

Griffin Percy P Dimitry Julie M JM Sheehan Patrick W PW Lananna Brian V BV Guo Chun C Robinette Michelle L ML Hayes Matthew E ME Cedeño Michelle R MR Nadarajah Collin J CJ Ezerskiy Lubov A LA Colonna Marco M Zhang Jinsong J Bauer Adam Q AQ Burris Thomas P TP Musiek Erik S ES

Proceedings of the National Academy of Sciences of the United States of America 20190221 11

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immuno ...[more]

PMID: 30792350

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Project description:BackgroundCircadian disturbance is a common nonmotor complaint in Parkinson's disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis.MethodsWe first examined the diurnal Rev-erbα rhythms and diurnal changes in microglia-mediated inflammatory cytokines expression in the SN of MPTP-induced PD mice. Further, we used BV2 cell to investigate the impacts of Rev-erbα on NLRP3 inflammasome and microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail.ResultsBV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system.ConclusionsThese observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.

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Circadian clock protein Rev-erb? regulates neuroinflammation.

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Circadian clock protein Rev-erbα regulates neuroinflammation.

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