Nrf2 selectively regulates IL-22 and IL-17A production in Th17 cells

Abstract

Abstract Th17 cell-derived IL-17A and IL-22 are critical for mounting both inflammatory and tissue protective responses. It remains unclear whether cytokine responses can be modified differently to achieve targeted functional outcome. A therapeutic strategy which inhibits CD4+ T cell-derived inflammatory IL-17A responses but concomitantly promotes IL-22-dependent tissue protective or regenerative response is of great clinical significance. Here, we showed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) selectively regulated IL-17A and IL-22 responses in CD4+ T cells. We found that Nrf2−/− mice had reduced IL-22 responses in Ovaalbumin (Ova) + LPS and separately concanavalin A (Con A) administered mice. Furthermore, CDDO-Im, a selective Nrf2 activator, induced IL-22 but suppressed IL-17A response in CD4+ T cells polarized under Th17 cell condition. Our qPCR data revealed that CDDO-Im-activated CD4+ T cells had lower Rorc, but increased Cybb, Sod1 and Sod3 transcript. The expression pattern of Il23r and Sod2 was unaltered. CDDO-Im-dependent IL-17A but not IL-22 response was regulated by Sod3. Interestingly, we found that CDDO-Im induced aryl hydrocarbon receptor (Ahr) and its downstream Cyp1a1 and Cyp1b1 gene expression. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity in a dose-dependent manner. Additionally, CDDO-Im induced Nqo1 expression, a Nrf2-activated gene, in WT mice but not in Ahr−/− mice. Finally, we confirmed that the CDDO-Immediated induction of IL-22 production in CD4+ T cells was abrogated in Ahr−/− mice. Collectively, our data show that Nrf2 promotes IL-22 production while it inhibits IL-17A expression in Th17 cells.