Nrf2 through Aryl Hydrocarbon Receptor Regulates IL-22 Response in CD4 T Cells.

IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-β and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that , , and genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of and inhibited -dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4 T cells was abrogated in CD4-specific knockout mice ( ). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4 T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4 T cells.