Ligand and transcriptional regulation of the nuclear receptor RORa on TH17 cell development and inflammation

SUMMARY The goal of our studies is to understand RORα’s role in the transcriptional regulation of TH17 cell pathogenicity and chronic inflammation. RORα is a member of the ligand-regulated nuclear receptor (NR) superfamily of transcription factors. Significantly less is known about RORα in the transcriptional regulation of TH17-mediated immunity. We and others recently published RORα is required for full TH17-cell development, particularly in mouse models of chronic inflammation. Despite this evidence, RORα is considered functionally redundant to RORγt, the lineage defining transcription factor of TH17 cells. As ligand-regulated transcription factors, NRs evolved to respond to endogenous small molecules, translating these signals into changes in gene expression. Synthetic small molecules can also be utilized to understand receptor function. Our data suggests that RORα/ligand-regulation may protect from chronic inflammation, including colitis. Given the evidence that both intra- and extra- cellular ligands regulate NR activity in TH17 cells, defining RORα and ligand mechanisms of action is key to understanding signaling pathways underlying homeostasis vs. pathogenesis. Therefore, understanding these processes may be essential to understand how RORα contributes to TH17 cells and disease. Our overarching goals are to elucidate the mechanisms that regulate RORα’s transcriptional activity and interacting partners, thus driving functionality in TH17 cells during inflammatory processes. Understanding RORα’s transcriptional role in TH17 cells may reveal a novel therapeutic option for the treatment of TH17-mediated chronic inflammatory disorders. We will achieve our goals by: 1) establishing how RORα transcriptionally promotes and maintains pathogenic TH17- mediated inflammation and 2) using pharmacological approaches to understand how ligands affect the transcriptional activity of RORα in TH17 cells. Collectively, our studies will uncover important transcriptional roles for RORα in TH17 cell biology and reveal whether targeting RORα may be advantageous for the treatment of TH17-mediated chronic inflammation.