Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY 11794.
Translational Health Science and Technology Institute, Faridabad, Haryana 12100, India.
J Immunol. 2021 Apr 1;206(7):1540-1548. doi: 10.4049/jimmunol.1900656. Epub 2021 Mar 1.
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 , , and genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of and inhibited -dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated 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 knockout mice ( ). 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.
IL-17A 和 IL-22 来源于 Th17 细胞，在黏膜免疫和炎症中发挥重要作用。TGF-β 和 IL-6 促进 Th17 细胞分化；然而，这些细胞因子有多个靶点。鉴定和筛选在某些炎症条件下调节 IL-17A 和 IL-22 反应的其他分子具有重要的临床意义。在本研究中，我们表明，特异性 Nrf2 激活剂 CDDO-Im 促进小鼠 Th17 细胞中 IL-17A 和 IL-22 的反应。相反，CDDO-Im 抑制多发性硬化症患者来源的 PBMC 中的 IL-17A 反应。然而，Nrf2 特异性调节体内的 IL-22 反应。Nrf2 通过调节靶基因中的抗氧化反应元件 (ARE) 结合基序来诱导或抑制转录。启动子分析表明， ， 和 基因有几个 ARE 基序。我们表明，Nrf2 与 和 的 ARE 阻遏物 (ARE-R2) 结合，并抑制 - 依赖性 IL-17A 反式激活。荧光素酶报告基因检测数据表明，CDDO-Im 调节 启动子活性。染色质免疫沉淀定量 PCR 数据表明，Nrf2 与 AhR 的 ARE 结合。最后，我们证实 CD4 特异性 敲除小鼠 ( ) 中 CD4 T 细胞中 CDDO-Im 介导的 IL-22 产生的诱导作用被消除。AhR 特异性拮抗剂 CH-223191 抑制 CD4 T 细胞中 CDDO-Im 诱导的 IL-22 产生，进一步证实了 AhR 依赖性调节。总之，我们的数据表明，Nrf2 通过 AhR 途径调节 CD4 T 细胞中的 IL-22 反应。
