Targeting Nuclear Receptors for TH17-Mediated Inflammation: REV-ERBerations of Circadian Rhythm and Metabolism.

Since their discovery, a significant amount of progress has been made understanding T helper 17 (TH17) cells' roles in immune homeostasis and disease. Outside of classical cytokine signaling, environmental and cellular intrinsic factors, including metabolism, have proven to be critical for non-pathogenic vs pathogenic TH17 cell development, clearance of infections, and disease. The nuclear receptor RORγt has been identified as a key regulator of TH17-mediated inflammation. Nuclear receptors regulate a variety of physiological processes, ranging from reproduction to the circadian rhythm, immunity to metabolism. Outside of RORγt, the roles of other nuclear receptors in TH17-mediated immunity are not as well established. In this mini-review we describe recent studies that revealed a role for a different member of the nuclear receptor superfamily, REV-ERBα, in the regulation of TH17 cells and autoimmunity. We highlight similarities and differences between reports, potential roles beyond TH17-mediated cytokine regulation, unresolved questions in the field, as well as the translational potential of targeting REV-ERBα.

High throughput screening for compounds to the orphan nuclear receptor NR2F6.

NR2F6 is considered an orphan nuclear receptor since its endogenous ligand has yet to be identified. Recently, NR2F6 has emerged as a novel cancer therapeutic target. NR2F6 has been demonstrated to be upregulated or overexpressed in several cancers. Importantly, Nr2f6-/- mice spontaneously reject tumors and develop host-protective immunological memory, a consequence of NR2F6 acting as an immune checkpoint in effector T cells. Collectively, these data suggest that modulation of NR2F6 activity may have important clinical applications in the fight against cancer. The nuclear receptor superfamily of ligand-regulated transcription factors has proven to be an excellent source of targets for therapeutic intervention of a broad range of diseases. Approximately 15% of FDA approved drugs target NRs, demonstrating their clinical efficacy. To identify small molecule regulators of NR2F6 activity, with the overall goal of immuno-oncology, we developed and initiated a high-throughput cell-based assay that specifically measures the transcriptional activity of NR2F6. We completed automated screening of approximately 666,000 compounds and identified 5,008 initial hits. Further screening efforts, including counterscreening assays, confirmed 128 of these hits, most of which had IC50s of equal to or less than 5µM potencies. Here, we report, for the first time, the identification of several small molecule compounds to the orphan nuclear receptor, NR2F6.

A Compass to Guide Insights into TH17 Cellular Metabolism and Autoimmunity.

T cells rapidly convert their cellular metabolic requirements upon activation, switching to a highly glycolytic program to satisfy their increasingly complex energy needs. Fundamental metabolic differences have been established for the development of Foxp3+ T regulatory (Treg) cells versus TH17 cells, alterations of which can drive disease. TH17 cell dysregulation is a driver of autoimmunity and chronic inflammation, contributing to pathogenesis in diseases such as multiple sclerosis. A recent paper published in Cell by Wagner, et al. combined scRNA-seq and metabolic mapping data to interrogate potential metabolic modulators of TH17 cell pathogenicity. This Compass to TH17 cell metabolism highlights the polyamine pathway as a critical regulator of TH17/Treg cell function, signifying its potential as a therapeutic target.