Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
Department of Dermatology and Venereology, Shenzhen Hospital, Peking University, Shenzhen, China.
Hepatology. 2018 Mar;67(3):1027-1040. doi: 10.1002/hep.29573. Epub 2018 Feb 1.
Interleukin-22 (IL-22), as a link between leukocytic and nonleukocytic cells, has gained increasing attention for its pronounced tissue-protective properties. MicroRNAs, emerging as crucial immune modulators, have been reported to be involved in the production and action of various cytokines. However, the precise control of IL-22 by microRNAs and its subsequent actions remained to be elucidated. In this study, we found a negative correlation between the expression of microRNA 15a/16-1 (miR-15a/16-1) and IL-22 in the model of concanavalin A-induced, immune-mediated liver injury. Knockout of miR-15a/16-1 ameliorated liver injury in an IL-22-dependent manner. Further results revealed that cluster of differentiation 4-positive (CD4 ) T cells were the major source of IL-22 during liver injury and that the aryl hydrocarbon receptor was the direct target of miR-15a/16-1 in CD4 T cells. In vivo and in vitro data showed that miR-15a/16-1 knockout CD4 T cells produced more IL-22, while overexpression of miR-15a/16-1 down-regulated the IL-22 production by inhibiting the aryl hydrocarbon receptor. Moreover, transfer of miR-15a/16-1 knockout CD4 T cells promoted tissue repair compared to wild-type CD4 T cells by up-regulating IL-22. In addition, as a synergistic effect, IL-22 could down-regulate miR-15a/16-1 expression by activating phosphorylated signal transducer and activator of transcription 3-c-myc signaling, and the decrease of miR-15a/16-1 in damaged hepatocytes contributed to IL-22-mediated tissue repair by reducing cell apoptosis and promoting cell proliferation. As further proof, we demonstrated the role of miR-15a/16-1 in controlling IL-22 production and IL-22-mediated reconstruction of the intestinal epithelial barrier in a dextran sodium sulfate-induced colitis model.
Our results suggest that miR-15a/16-1 acts as a essential regulator of IL-22 and that the miR-15a/16-1-aryl hydrocarbon receptor-IL-22 regulatory axis plays a central role in tissue repair; modulation of miR-15a/16-1 might hold promise in developing new strategies to enhance IL-22-mediated tissue repair. (Hepatology 2018;67:1027-1040).
白细胞介素 22（IL-22）作为白细胞和非白细胞细胞之间的联系，因其明显的组织保护特性而受到越来越多的关注。微小 RNA（miRNA）作为重要的免疫调节剂，已被报道参与各种细胞因子的产生和作用。然而，miRNA 对 IL-22 的精确调控及其后续作用仍有待阐明。在这项研究中，我们发现在伴刀豆球蛋白 A 诱导的免疫介导的肝损伤模型中，miR-15a/16-1 的表达与 IL-22 呈负相关。miR-15a/16-1 的敲除以 IL-22 依赖的方式改善了肝损伤。进一步的结果表明，在肝损伤过程中，CD4+T 细胞是 IL-22 的主要来源，而芳香烃受体是 CD4+T 细胞中 miR-15a/16-1 的直接靶标。体内和体外数据表明，miR-15a/16-1 敲除的 CD4+T 细胞产生更多的 IL-22，而 miR-15a/16-1 的过表达通过抑制芳香烃受体下调 IL-22 的产生。此外，与野生型 CD4+T 细胞相比，miR-15a/16-1 敲除的 CD4+T 细胞通过上调 IL-22 促进组织修复。此外，作为协同效应，IL-22 通过激活磷酸化信号转导和转录激活因子 3-c-myc 信号下调 miR-15a/16-1 的表达，而受损肝细胞中 miR-15a/16-1 的减少通过减少细胞凋亡和促进细胞增殖有助于 IL-22 介导的组织修复。作为进一步的证据，我们证明了 miR-15a/16-1 在控制白细胞介素 22 的产生和白细胞介素 22 介导的葡聚糖硫酸钠诱导的结肠炎模型中肠上皮屏障重建中的作用。
我们的结果表明，miR-15a/16-1 作为白细胞介素 22 的重要调节因子发挥作用，miR-15a/16-1-芳香烃受体-白细胞介素 22 调节轴在组织修复中起核心作用；miR-15a/16-1 的调节可能为增强白细胞介素 22 介导的组织修复提供新的策略。（《肝脏病学》2018；67：1027-1040）。
