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Inhibition of microRNA-155 ameliorates experimental autoimmune myocarditis by modulating Th17/Treg immune response

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Abstract

Experimental autoimmune myocarditis (EAM) is an inflammatory cardiac disease driven by autoantigen-specific CD4+ T cells. Th17 and Treg cells are crucial participants in immune response. A wide variety of immune disorders are associated with Th17/Treg imbalance. MicroRNA-155 (miR-155) is a pivotal regulator of the immune system. However, the modulatory effect of miR-155 on Th17/Treg immune response during EAM is unknown. Our study aims to investigate the potential role of miR-155 on the development of autoimmune myocarditis. In this study, we revealed that miR-155 expression was highly elevated in heart tissue and CD4+ T cells during EAM. Also, we identified a proliferative and functional imbalance of Th17/Treg in EAM, which is due to a more active development of Th17 cells and an increased resistance of Th17 cells to Treg-mediated suppression. MiR-155 inhibition in EAM resulted in attenuated severity of disease and cardiac injury, reduced Th17 immune response, and decreased dendritic cell (DC) function of secreting Th17-polarizing cytokines. Furthermore, CD4+ T cells from miR-155-inhibited EAM mice exhibited reduced proliferation and IL-17A secretion in response to autoantigen. Finally, we confirmed an indispensable positive role of miR-155 on the differentiation of Th17 cells and the DC function of secreting Th17-polarizing cytokines through in vitro studies. These findings demonstrated that miR-155 adversely promotes EAM by driving a Th17/Treg imbalance in favor of Th17 cells, and anti-miR-155 treatment can significantly reduce the autoimmune response thus to ameliorate EAM, suggesting that miR-155 inhibition could be a promising therapeutic strategy for the treatment of autoimmune myocarditis.

Key message

  • MiR-155 expression was highly elevated in EAM mice.

  • An imbalance of Th17/Treg existed in EAM mice.

  • MiR-155 inhibition in EAM attenuated disease severity and cardiac injury.

  • MiR-155 inhibition suppressed Th17 immune response in EAM.

  • MiR-155 inhibition reduced DC function of secreting Th17-polarizing cytokines in EAM.

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Acknowledgments

We are grateful to all the members and the facilities of the experimental animal center of the Tongji Medical College for excellent animal care. This project was supported by grant from the National Natural Science Foundation of China (No. 81170205).

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    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tong Ji Medical College of Huahzong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022, China

      Lianhua Yan, Fen Hu, Xiaofei Yan, Yuzhen Wei, Wenhan Ma, Ya Wang, Shuai Lu & Zhaohui Wang

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    1. Lianhua Yan
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    Lianhua Yan and Fen Hu contributed equally to this work.

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    Yan, L., Hu, F., Yan, X. et al. Inhibition of microRNA-155 ameliorates experimental autoimmune myocarditis by modulating Th17/Treg immune response. J Mol Med 94, 1063–1079 (2016). https://doi.org/10.1007/s00109-016-1414-3

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