REV-ERB-dependent heme signaling regulates Th17 cell activity

Abstract

Abstract T helper 17 (Th17) cells are important for protective immunity at mucosal surfaces, but their dysregulation is implicated in the pathogenesis of autoimmune and chronic inflammatory diseases. A better understanding of the signaling pathways governing Th17 cell-mediated immunity and pathogenicity would aid in the development of novel therapeutics to treat Th17 cell-mediated diseases. We recently showed that the REV-ERB nuclear receptors (REV-ERBα and REV-ERBβ) are critical regulators of Th17 cell development and pathogenicity. As ligand-regulated transcription factors, the REV-ERBs can bind their natural ligand, heme, which modulates REV-ERB function. To investigate heme’s role as a REV-ERB-dependent signaling molecule in Th17 cells, we differentiated naive CD4+ T cells under Th17-polarizing conditions and found heme treatment repressed differentiation. Repression was partially ablated in cells lacking the REV-ERBs, indicating heme can specifically activate the REV-ERBs in Th17 cells. We further found that enzymes involved in heme biosynthesis and transport were upregulated during Th17 cell differentiation, indicating heme is actively produced in Th17 cells. To investigate the role of endogenous heme, we overexpressed REV-ERB mutants incapable of binding heme, which relieved repression of Th17 cell differentiation relative to over expression of wild type (WT) REV-ERBs. RNA-seq of mutant- vs WT-overexpressed cells revealed that heme modulates a specific subset of REV-ERB target genes. Together, our findings suggest that conditions affecting heme levels in Th17 cells can alter the transcriptional phenotype of the cell via heme modulation of REV-ERB activity.