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

Abstract

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 Il17a, Rorc, and Ahr genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of Rorc and inhibited Rorc-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated Ahr 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 Ahr knockout mice (AhrCD4). 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.

Sustained AhR activity programs memory fate of early effector CD8 + T cells

“…S2 D ). In addition to STAT3, nuclear factor-erythroid 2-related-2 (Nrf2) can also transactivate AhR expression ( 25 , 26 ). We found that although hardly detectable in naive T cells, Nrf2 was rapidly up-regulated in T eff cells ( Fig.…”

Diagnostic Value of Serum Levels of IL-22, IL-23, and IL-17 for Idiopathic Pulmonary Fibrosis Associated with Lung Cancer

“…There are studies about whether IL-17 could serve as biomarkers for cancer; however, the results have been controversial. In the field of lung cancer studies, it has been reported that the expression level of IL-17 is elevated in the serum of patients, and the level of IL-17 in the serum of the patients may function as a prognostic marker, 15 , 22–24 while on the other hand, some other studies had shown that the levels of IL-17 did not show differences between the patients and healthy controls. In the present study, we observed that the serum level of IL-17 was significantly upregulated in the serum of the patients in comparison with the healthy control group.…”

The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis

“…Moreover, tBHQ induced an Nrf2-dependent increase in IgM secretion by LPS-stimulated B cells ( 106 ). Meanwhile, studies have shown that Nrf2 can regulate the IL-22 response in CD4 + T cells through the AhR pathway ( 107 ). This suggests that activation of Nrf2 has a relevant role in regulating both T and B cells.…”