The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease

Abstract T helper 17 cells (Th17) play an important role in controlling extracellular bacteria and yeast infections; however, dysregulated Th17 response can lead to detrimental autoimmune diseases such as multiple sclerosis. Th17 cell differentiation relies on IL6/TGF-β-induced expression of retinoic acid receptor-related orphan nuclear receptor RORγt, which is able to induce Th17 effector cytokines such as IL17A. Therefore, antagonizing RORγt activity may prove to be one of the therapeutic strategies for ameliorating Th17-mediated inflammation. Here we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt-induced Il17a expression. Both RORγt and REV-ERBα bind to the same ROR response element (RORE) in Il17a promoter region. Elevated expression of REV-ERBα prevents RORγt binding to RORE and reduces Il17a expression. Furthermore, treatment with a synthetic REV-ERBα agonist, SR9009, significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. These results suggest that modulating REV-ERBα activity holds therapeutic potential for treatment of Th17 cell-mediated autoimmune diseases.