Circadian clock protein Rev-erbα regulates neuroinflammation

Percy Griffin, Julie M. Dimitry, Patrick W. Sheehan, Brian V. Lananna, Chun Guo, Michelle L. Robinette, Matthew E. Hayes, Michelle R. Cedeño, Collin J. Nadarajah, Lubov A. Ezerskiy, Marco Colonna, Jinsong Zhang, Adam Q. Bauer, Thomas P. Burris, Erik S. Musiek

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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-erbα, 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, whichwas disrupted in Rev-erbα -/- mice. Rev-erbα 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-erbα -/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα -/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Reverbα physically interacts with the promoter regions of several NF- κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Reverbα -/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPSinduced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media fromRev-erbαdeficient primary glial cultures exacerbated oxidative damage in cultured neurons. Reverbα -/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Original languageEnglish
Pages (from-to)5102-5107
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number11
DOIs
StatePublished - 2019

Keywords

  • Circadian
  • Microglia
  • Neuroinflammation
  • Rev-erbα

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