TY - JOUR
T1 - Nrf2 through aryl hydrocarbon receptor regulates IL-22 Response in CD4+T Cells
AU - Lin, Xun
AU - Tawch, Suzanne
AU - Wong, Hoi Tong
AU - Roy, Suyasha
AU - Gaudino, Stephen
AU - Castillo, Patricia
AU - Elsegeiny, Waleed
AU - Wakabayashi, Nobunao
AU - Oury, Tim D.
AU - Pociask, Derek
AU - Chen, Kong
AU - McLinskey, Nancy
AU - Melville, Patricia
AU - Syritsyna, Olga
AU - Coyle, Patricia
AU - Good, Misty
AU - Awasthi, Amit
AU - Kolls, Jay K.
AU - Kumar, Pawan
N1 - Funding Information:
of Health Grant R21 AI146696 (to P.K.), Division of Intramural Research/National Institute of Allergy and Infectious Diseases Grant R21 AI149257 (to P.K.), and the State University of New York Research Foundation (to P.K.). A.A. was supported by Wellcome Trust/Department of Biotechnology India Alliance Intermediate Fellowship IA/I/12/1/500524 and the Department of Science and Technology Science and Engineering Research Board of the Government of India.
Funding Information:
This work was supported by Crohn's and Colitis Foundation Grant 476637 (to P.K.), National Multiple Sclerosis Society Grant PP-1709-29192 (to P.K.), National Institues of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grants R01 DK121798-01 (to P.K.) and R01DK118568 (to M.G.), National Institutes of Health Grant R21 AI146696 (to P.K.), Division of Intramural Research/National Institute of Allergy and Infectious Diseases Grant R21 AI149257 (to P.K.), and the State University of New York Research Foundation (to P.K.). A.A. was supported by Wellcome Trust/Department of Biotechnology India Alliance Intermediate Fellowship IA/I/12/1/500524 and the Department of Science and Technology Science and Engineering Research Board of the Government of India.
Funding Information:
This work was supported by Crohn’s and Colitis Foundation Grant 476637 (to P.K.), National Multiple Sclerosis Society Grant PP-1709-29192 (to P.K.), National Insti-tues of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grants R01 DK121798-01 (to P.K.) and R01DK118568 (to M.G.), National Institutes
Publisher Copyright:
© 2021 American Association of Immunologists. All rights reserved.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-b 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 CDDOIm- 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.
AB - IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-b 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 CDDOIm- 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.
UR - http://www.scopus.com/inward/record.url?scp=85103074551&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1900656
DO - 10.4049/jimmunol.1900656
M3 - Article
C2 - 33648937
AN - SCOPUS:85103074551
VL - 206
SP - 1540
EP - 1548
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -