SUMMARY As ligand-regulated transcription factors, nuclear receptors (NRs) evolved to respond to natural small molecules, such as vitamins and lipids, translating endocrine and metabolic signals into changes in gene expression. Our data, that ligand-dependent REV-ERB activity may regulate TH17 cell inflammatory responses, suggests that the REV-ERBs natural endogenous ligand, heme, may function as a REV-ERB-dependent signaling molecule in TH17 cells. Given the evidence that both intracellular and extracellular ligands regulate NR activity in TH17 cells, defining ligand mechanisms of action and/or understanding the source and effects of heme- dependent REV-ERB activity in TH17 cells may reveal signaling pathways underlying homeostasis vs. pathogenesis. Our preliminary data suggests that REV-ERBa/heme dependent signaling may be required for protection from inflammation in the gut (colitis). This coincides with recent evidence demonstrating that dietary heme induces gut dysbiosis and aggravates colitis. Therefore, understanding how ligands, like heme, regulate the REV-ERBs would be particularly valuable for understanding how environmental signals influence TH17 cells and inflammation. Our overarching goals are to define the role of heme as an endocrine signaling molecule and elucidate the ligand-mediated mechanisms that regulate REV-ERBa’s transcriptional activity and interacting partners, thus driving repressive functions in TH17 cells during inflammatory processes. We will accomplish this goal by identify heme’s role as a REV-ERBa-dependent signaling molecule in TH17 cells; establishing whether heme-dependent REV-ERBa activity affects TH17-mediated inflammation in vivo; and defining how ligands affect the REV-ERBa’s transcriptional partners and repressive function in TH17 cells. The proposed studies will address fundamental questions regarding ligand-dependent REV-ERBa activity. Importantly, these insights will be particularly valuable in understanding TH17-mediated disease development and may inform on future pharmaceutical approaches.