Natural Compound 2,2',4'-Trihydroxychalcone Suppresses T Helper 17 Cell Differentiation and Disease Progression by Inhibiting Retinoid-Related Orphan Receptor Gamma T

Retinoid-related orphan receptor gamma t (ROR gamma t), a vital transcription factor for the differentiation of the pro-inflammatory Th17 cells, is essential to the inflammatory response and pathological process mediated by Th17 cells. Pharmacological inhibition of the nuclear receptor ROR gamma t provides novel immunomodulators for treating Th17-driven autoimmune diseases and organ transplant rejection. Here, we identified 2,2',4'-trihydroxychalcone (TDC), a natural chalcone derivant, binds directly to the ligand binding domain (LBD) of ROR gamma t and inhibited its transcriptional activation activity. Using three mice models of Th17-related diseases, it was found that the administration of TDC effectively alleviated the disease development of experimental autoimmune encephalomyelitis (EAE), experimental colitis, and skin allograft rejection. Collectively, these results demonstrated TDC targeting ROR gamma t to suppress Th17 cell polarization, as well as its activity, thus, indicating the potential of this compound in treating of Th17-related autoimmune disorders and organ transplant rejection disorders.

Automated summary

ROR gamma t is a crucial transcription factor for the differentiation of pro-inflammatory Th17 cells. In this study, a natural compound called 2,2',4'-trihydroxychalcone (TDC) was found to directly bind to the ligand binding domain of ROR gamma t and inhibit its transcriptional activation activity. TDC administration effectively alleviated the disease development in three different mouse models of Th17-related diseases.