Investigating heme regulation of REV-ERBα activity in Th17 cells

Abstract T helper 17 (Th17) cell dysregulation is implicated in the pathogenesis of autoimmune and chronic inflammatory diseases. Because current therapeutics exhibit negative side effects or are only successful in small patient subsets, there is a need to identify better Th17 cell-specific drug targets. We recently showed that the nuclear receptor (NR) REV-ERBα represses Th17 cell development and pathogenesis. As ligand-regulated transcription factors, NRs like REV-ERBα are amenable to pharmacological modulation, making REV-ERBα a viable target for the treatment of Th17 cell-mediated diseases. However, the mechanisms underlying ligand regulation of REV-ERBα in Th17 cells remain unclear. REV-ERBα-mediated repression of target genes is enhanced by its endogenous ligand, heme, in other cell types, but heme’s role in Th17 cells is largely unexplored. To investigate heme’s role in Th17 cells, we differentiated naïve CD4+ T cells under Th17-polarizing conditions in vitro and found heme treatment repressed differentiation. To assess whether the effect was due to activation of REV-ERBα, we heme-treated cells lacking REV-ERBα and found the repression was partially ablated. We also found that overexpression of a REV-ERBα mutant incapable of binding heme relieved repression of Th17 cell differentiation relative to overexpression of wild type REV-ERBα. Our findings suggest that heme negatively regulates Th17 cell development, in part by activating REV-ERBα, which may require heme binding to repress target genes. Characterizing REV-ERBα regulation by heme may offer insight into mechanisms of Th17 cell pathogenesis, as well as inform the design of therapeutics for autoimmune and chronic inflammatory diseases.