Circadian clock protein Rev-erbα 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-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, which was 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 from Rev-erbα-deficient 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.Rev-erbα | circadian | microglia | neuroinflammation C ircadian clocks allow organisms to precisely synchronize internal physiological processes with their external environment. A conserved transcriptional-translational feedback loop known as the core circadian clock controls cycles of protein expression that produce transcriptional and physiologic rhythms. This core circadian clock consists of the transcriptional activators BMAL1 and CLOCK, which drive transcription of their own transcriptional repressors, including CRYPTOCHROME (CRY), PE-RIOD (PER), and REV-ERB proteins (1). The circadian system regulates a variety of critical cellular processes, including aspects of metabolism, inflammation, and redox homeostasis (2). Disruptions of the clock or its associated proteins have been implicated in pathological conditions ranging from cancer to neurodegenerative diseases (2-4). However, the roles of cellular circadian clocks in brain health and neuroinflammation are still poorly understood.Aberrant glial cell activation and neuroinflammation are hallmarks of many neuro...

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

“…Interestingly, REV‐ERBα‐deficient mice highly expressed Iba1 and CD68 as markers of microglia and phagocytic microglia, respectively, in the brain (Figure g). A previous report also showed significantly increased Iba1 and CD68 expression in hippocampal microglia of REV‐ERBα knockout mice (Griffin et al, ). Thus, we suspect that high levels of phagocytic microglia, evoked by REV‐ERBα depletion, are likely responsible for the marked decrease in plaque accumulation in RKO/5XFAD mice.…”

“…Interestingly, SR8278 significantly increased the expression of DAP12 which is considered as TREM2 adaptor in microglia, as well as induced TREM2 levels, indicating that SR8278 could propagate TREM2 downstream signaling in microglia. TREM2 induction was also seen following REV-ERBα deletion in another paper (Griffin et al, 2019). Moreover, numerous studies support that TREM2 has critical role on tauopathy and amyloid pathology (Leyns et al, 2019).…”

“…These proteins drive the transcription of several clock-related genes including Period (Per1/2/3), Cryptochrome (Cry1/2), REV-ERB proteins (Nr1d1/Nr1d2 encode REV-ERBα/REV-ERBβ), and retinoic acid receptor-related orphan receptors (e.g., Rora). Of these, REV-ERBα and β transcriptionally repress Bmal1 by binding to the RORE cis-element in its promoter region (Herzog, Hermanstyne, Smyllie, & Hastings, 2017) and connect the circadian system to macrophage-driven inflammation (Gibbs et al, 2012;Griffin et al, 2019;Pariollaud et al, 2018). Rev-Erbα/β are also nuclear receptors which function as transcriptional repressors and exert a variety of biological functions (Everett & Lazar, 2014;Lam et al, 2013;Woldt et al, 2013).…”

“…Rev-Erbα/β are also nuclear receptors which function as transcriptional repressors and exert a variety of biological functions (Everett & Lazar, 2014;Lam et al, 2013;Woldt et al, 2013). Recent studies suggest that modulating REV-ERBα activity can be a potent therapeutic target for neurodegenerative disease such as AD via modulating the glia activity and neuroinflammation response (Griffin et al, 2019;Roby et al, 2019).…”

REV-ERBα mediates complement expression and circadian regulation of microglial synaptic phagocytosis

“…Deletion of BMAL1 abrogates circadian clock function and leads to an 85% decrease in REV-ERB expression in the brain (Musiek et al, 2013). REV-ERB functions as a transcriptional repressor in many tissues, and has been implicated in regulation of metabolism and inflammation (Everett and Lazar, 2014) Previous work from our group shows that deletion of BMAL1 or its downstream target REV-ERB causes neuroinflammation and impaired brain functional connectivity (Griffin et al, 2019;Musiek et al, 2013). Diminished BMAL1 and REV-ERB expression have also been described in mouse models of Alzheimer's Disease (AD) (Lee et al, 2020;Stevanovic et al, 2017).…”