The REV-ERBs: Negative Regulators of Th17 Cell Development and Autoimmunity

Abstract

Abstract Th17 cells have been associated with the pathogenesis of several autoimmune diseases, including multiple sclerosis. While the nuclear receptor (NR) RORγt is considered the lineage determining transcription factor for Th17 cells, the REV-ERBs (REV-ERBα and REV-ERBβ), two other members of the NR superfamily, are often co-expressed in the same tissues as members of the ROR subfamily of NRs (i.e. RORγt) and bind to the same DNA response elements. In contrast to the RORs, which are transcriptional activators, the REV-ERBs are transcriptional repressors, suggesting mutual cross talk and co-regulation of their shared target genes. While the REV-ERBs are best known for their roles in the circadian rhythm and metabolic processes, their role in Th17 cell development and Th17 mediated inflammatory diseases is largely unexplored. Our data indicates that over expression of the REV-ERBs inhibits Th17 cell differentiation whereas genetic deletion of the REV-ERBs perturbs Th17 cell differentiation. Using two commonly used mouse models of autoimmunity known to be Th17 driven [experimental autoimmune encephalomyelitis (EAE) and adoptive transfer model of colitis], we found that loss of REV-ERB expression exacerbates EAE and colitis compared to WT controls, largely as a consequence of an increased number of pro-inflammatory Th17 cells. Finally, using REV-ERB-selective small molecules that we have developed, we discovered that pharmacological modulation of REV-ERB activity significantly inhibits the development of autoimmunity. Overall, our data suggests that the REV-ERBs are potent negative regulators of Th17 differentiation and identifies the REV-ERBs as viable therapeutic targets for the treatment of Th17-mediated autoimmune diseases.