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.

• Authors: Xun Lin, Suzanne Tawch, Hoi Tong Wong, Suyasha Roy, Stephen Gaudino, Patricia Castillo, Waleed Elsegeiny, Nobunao Wakabayashi, Tim D Oury, Derek Pociask, Kong Chen, Nancy McLinskey, Patricia Melville, Olga Syritsyna, Patricia Coyle, Misty Good, Amit Awasthi, Jay K Kolls, Pawan Kumar
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 206 Issue 7 Pg. 1540-1548 (04 01 2021) ISSN: 1550-6606 [Electronic] United States
• PMID: 33648937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Association of Immunologists, Inc.

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
• Azo Compounds
• Imidazoles
• Interleukin-17
• Interleukins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Pyrazoles
• Receptors, Aryl Hydrocarbon
• Rorc protein, mouse
• Oleanolic Acid

Topics

• Animals
• Azo Compounds (metabolism)
• CD4-Positive T-Lymphocytes (immunology)
• Gene Expression Regulation
• Humans
• Imidazoles (metabolism)
• Interleukin-17 (genetics, metabolism)
• Interleukins (metabolism)
• Lymphocyte Activation
• Mice
• Mice, Knockout
• Multiple Sclerosis (immunology)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Nuclear Receptor Subfamily 1, Group F, Member 3 (genetics)
• Oleanolic Acid (analogs & derivatives, metabolism)
• Promoter Regions, Genetic (genetics)
• Pyrazoles (metabolism)
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Signal Transduction
• Th17 Cells (immunology)
• Interleukin-22