Circadian clock protein Rev-erba regulates neuroinflammation

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 alpha, 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 alpha(-/-) mice. Rev-erb alpha 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 alpha(-/-) mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-kappa B signaling. Primary Rev-erb alpha(-/-) microglia exhibited proinflammatory phenotypes and increased basal NF-kappa B activation. Chromatin immunoprecipitation revealed that Rev-erb alpha physically interacts with the promoter regions of several NF kappa B-related genes in primary microglia. Loss of Rev-erb alpha in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erb alpha(-/-) 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 alpha deletion influenced neuronal health, as conditioned media from Rev-erb alpha-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erb alpha(-/-) mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erb alpha as a pharmacologically accessible link between the circadian clock and neuroinflammation.