Nrf2 differentially regulates pro- and anti-inflammatory function of Th17 cells through RORγT, SOD3 and Ahr

Abstract IL-17A and IL-22 derived from CD4+ T cells are significant for both inflammatory and tissue protective responses. However, it remains unclear whether IL-17A and IL-22 can be regulated differently to achieve targeted functional outcome. Here, we showed that Nrf2 selectively regulated IL-17A and IL-22 responses in CD4+ T cells. Nrf2−/− mice challenged with Ovalbumin (Ova) + LPS displayed reduced IL-22 but enhanced IL-17A response. Interestingly, CDDO-Im, a selective Nrf2 activator, induced IL-22 but suppressed IL-17A response in CD4+ T cells polarized under Th17 cell condition. CDDO-Im-activated CD4+ T cells had lower Rorc, but increased Cybb, Sod1 and Sod3 transcript. Luciferase reporter assay showed that IL-17A promoter activity is inhibited by Nrf2 at the presence of RORγT, suggesting that inhibition of IL-17A by Nrf2 is RORγT-dependent. CDDO-Im-impaired IL-17A response was also abolished in SOD3−/−, showing that SOD3 is involved in CDDO-Im-mediated inhibition of IL-17A. Furthermore, we found that CDDO-Im induced aryl hydrocarbon receptor (Ahr) and its downstream Cyp1a1 and Cyp1b1 gene expression. Additionally, CDDO-Im induced Nqo1 expression, an Nrf2-activated gene, in WT mice but not in Ahr−/− mice. CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in Ahr−/− mice, supporting that Ahr is involved in the induction of IL-22 by Nrf2. Finally, upon the stimulation of anti-CD3 and anti-CD28, CDDO-Im also mediated the inhibition of IL-17A but induction of IL-22 production in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, our data show that Nrf2 promotes IL-22 production via Ahr, whereas RORγT and SOD3 are involved in Nrf2-mediated inhibition of IL-17A expression in Th17 cells.