Retinoic Acid-Related Orphan Receptor (ROR) Inverse Agonists: Potential Therapeutic Strategies for Multiple Inflammatory Diseases?

Retinoic acid-related orphan receptors (RORs) function as ligand-dependent transcription factors. Several (oxy)sterols have been identified that activate or repress ROR transcriptional activity by functioning as either ROR agonists or inverse agonists. RORs are involved in the control of many biological processes, including the regulation of differentiation and function of neural, immune, and metabolic tissues, bone, and heart. Many of the processes and functions regulated by RORs play a critical role in various pathologies, including autoimmune and other inflammatory diseases, metabolic syndrome and diabetes, neurological and psychiatric disorders, and cardiac injury. Together, these studies raised the possibility that modulation of ROR activity by synthetic ligands might be a useful approach to intervene in these diseases. This led to the identification of many synthetic ROR (inverse) agonists that repress or induce ROR transcriptional activity. Most studies have been focusing on RORγt inverse agonists that repress the generation of interleukin 17 (IL-17)-producing immune cells and the production of pro-inflammatory cytokines, such as IL-17, which play a critical role in various inflammatory diseases. Treatment of autoimmune disease in several experimental rodent models with RORγ inverse agonists was shown to reduce the production of pro-inflammatory cytokines and ameliorate the disease. Thus, ROR (inverse) agonists may potentially provide new therapeutic strategies to treat various pathologies.