Dataset Information

REV-ERBα Regulates T_H17 Cell Development and Autoimmunity.

ABSTRACT: RORγt is well recognized as the lineage-defining transcription factor for T helper 17 (T_H17) cell development. However, the cell-intrinsic mechanisms that negatively regulate T_H17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in T_H17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates T_H17 cell development via repression of genes traditionally characterized as RORγt dependent, including Il17a. Deletion of REV-ERBα enhanced T_H17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed T_H17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBα negatively regulates pro-inflammatory T_H17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of T_H17-mediated autoimmune diseases.

SUBMITTER: Amir M

PROVIDER: S-EPMC6400287 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

REV-ERBα Regulates TH17 Cell Development and Autoimmunity.

Amir Mohammed M Chaudhari Sweena S Wang Ran R Campbell Sean S Mosure Sarah A SA Chopp Laura B LB Lu Qun Q Shang Jinsai J Pelletier Oliver B OB He Yuanjun Y Doebelin Christelle C Cameron Michael D MD Kojetin Douglas J DJ Kamenecka Theodore M TM Solt Laura A LA

Cell reports 20181201 13

RORγt is well recognized as the lineage-defining transcription factor for T helper 17 (TH17) cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in TH17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates TH17 cell development via ...[more]

PMID: 30590045

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Project description: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 Rev-erbα 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, Rev-erbα-/- 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-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- 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.

Dataset Information

REV-ERBα Regulates T_H17 Cell Development and Autoimmunity.

Publications

REV-ERBα Regulates T<sub>H</sub>17 Cell Development and Autoimmunity.

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