MiR-15a/16-1 Suppresses AHR-dependent IL-22 Secretion in CD4+ T cells and Contributes to Immune-mediated Organ Injury

Abstract

Interleukin-22 (IL-22), as a link between leukocytic and non-leukocytic cells, has gained increasing attention for its pronounced tissue-protective properties. MicroRNAs (miRNAs), 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 miRNAs and its subsequent actions remained to be elucidated. In this study, we found a negative correlation between the expression of miR-15a/16-1 and IL-22 in the model of concanavalinA (ConA)-induced immune-mediated liver injury. Knockout of miR-15a/16-1 (miR-15a/16-1-KO) ameliorated liver injury in an IL-22-dependent manner. Further results revealed that CD4⁺ T cells were the major source of IL-22 during liver injury, and aryl hydrocarbon receptor (AHR) 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-KO CD4⁺ T cells produced more IL-22, while overexpression of miR-15a/16-1 downregulated the IL-22 production by inhibiting AHR. Moreover, transfer of miR-15a/16-1-KO CD4⁺ T cells promoted tissue repair compared to wild type CD4⁺ T cells by upregulating IL-22. In addition, as a synergistic effect, IL-22 could downregulate miR-15a/16-1 expression via activating pSTAT3/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 intestinal epithelial barrier in a dextran sodium sulphate-induced colitis model. Conclusion: Our results suggest that miR-15a/16-1 acts as a novel essential regulator of IL-22, and the miR-15a/16-1-AHR-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. This article is protected by copyright. All rights reserved.

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