Inflammatory bowel diseases (IBD), including Crohn?s disease and ulcerative colitis are characterized by an inappropriate immune response to commensal gut flora that causes chronic damage to the gastrointestinal (GI) tract. Genome-wide association studies showing genes associated with T helper 17 (Th17) immune responses are strongly implicated in IBD susceptibility together with clinical evidence of Th17 cells in GI tissues of IBD patients have identified a central role for Th17 cells in IBD pathogenesis. Although Th17 cells are characterized by the production of IL-17A, they also produce many other molecules each with critical roles in regulating the immune response. This could explain why IL-17A-neutralizing antibodies have had little success in treating IBD, while targeting factors within Th17 cells that broadly regulate their expression of effector molecules may be a more effective strategy. To this end, we recently demonstrated that the closely related REV-ERB (REV-ERBa and REV-ERBb) nuclear receptors (NRs) are cell-intrinsic repressors of Th17 cell pathogenicity. Transcriptional repression of signature Th17 cell genes by the REV-ERBs is essential for limiting disease severity in mouse models of chronic inflammatory disease and treatment with synthetic REV-ERB ligands developed at Scripps Florida enhanced the protective effect. The porphyrin, heme, is the endogenous ligand for the REV-ERBs and my preliminary data indicate that heme is important for REV-ERB activity in Th17 cells. Since NR ligands evolved to transmit extracellular or intracellular signals into changes in gene expression, understanding the source and effects of heme-dependent REV-ERB activity in Th17 cells may reveal signaling pathways underlying IBD pathogenesis that could be exploited for therapeutic benefit. At the same time, although the basis for ligand- dependent NR activity is in their regulation of NR structure, contradictory evidence between published cell-based and structural studies has prevented understanding of the molecular basis for heme-dependent REV-ERB activity. My preliminary data reveal a potential solution to this conflict. My overarching hypothesis is that heme produced intracellularly in Th17 cells enhances REV-ERB repression of a pathogenic Th17 cell phenotype by stabilizing the REV-ERBs? interaction with a transcriptionally repressive coregulator (corepressor) protein. I will test this hypothesis through two central aims: 1) I will identify the role of heme as a REV-ERB-dependent signaling molecule in Th17 cells and 2) I will define the heme-dependent structural changes that influence REV-ERB activity. I expect the results of these aims to characterize an underexplored signaling pathway in Th17 cells that could be targeted to treat IBD. In the process, I will receive comprehensive training in immunology and structural biology approaches from a unique, interdisciplinary mentorship team. Together with the extensive professional development resources at Scripps Florida, this team will ensure that I progress toward achieving my long-term goal of directing a research lab studying the molecular basis of chronic inflammatory diseases such as IBD.
Since T helper 17 (Th17) cells have a central role in inflammatory bowel disease (IBD) pathogenesis, a better understanding of the signaling pathways regulating Th17 cell pathogenicity would help identify novel IBD treatment options. We recently showed that the REV-ERB nuclear receptors are cell-intrinsic repressors of Th17 cell pathogenicity in IBD, but the role of the natural REV-ERB ligand, heme, in Th17 cells remains unclear. This work will characterize the cellular and structural mechanisms underlying heme-dependent REV-ERB activity in IBD-associated Th17 cells, which will define an underexplored signaling pathway that could be exploited for IBD treatment.
