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Kruppel-like factor 10 protects against acute viral myocarditis by negatively regulating cardiac MCP-1 expression

Cellular & Molecular Immunology volume 18, pages 2236–2248 (2021)Cite this article

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Abstract

Viral myocarditis (VMC) is a cardiac disease associated with myocardial inflammation and injury induced by virus infection. Cardiomyocytes have recently been regarded as key players in eliciting and modulating inflammation within the myocardium. Kruppel-like factor 10 (KLF10) is a crucial regulator of various pathological processes and plays different roles in a variety of diseases. However, its role in VMC induced by coxsackievirus B3 (CVB3) infection remains unknown. In this study, we report that cardiac KLF10 confers enhanced protection against viral myocarditis. We found that KLF10 expression was downregulated upon CVB3 infection. KLF10 deficiency enhanced cardiac viral replication and aggravated VMC progress. Bone marrow chimera experiments indicated that KLF10 expression in nonhematopoietic cells was involved in the pathogenesis of VMC. We further identified MCP-1 as a novel target of KLF10 in cardiomyocytes, and KLF10 cooperated with histone deacetylase 1 (HDAC1) to negatively regulate MCP-1 expression by binding its promoter, leading to activation of MCP-1 transcription and recruitment of Ly6Chigh monocytes/macrophages into the myocardium. This novel mechanism of MCP-1 regulation by KLF10 might provide new insights into the pathogenesis of VMC and a potential therapeutic target for VMC.

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Acknowledgements

This work was supported by the Chinese National Natural Science Foundation (31400769, 31870903, 31870868, and 31670930), Jiangsu Province Natural Science Foundation (BK20140371) and Jiangsu Postdoctoral Science Foundation (1402176C), Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Institute of Biology and Medical Sciences, Soochow University, Building 703, 199 Ren-ai Road, 215123, Suzhou, China

    Jie Yang, Hongkai Zhang, Lin Wei, Yahui Song, Yuan Luo, Wei Xu & Min Li

  2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Xuelian Wang, Jing Guo & Lie Wang

  3. Central Laboratory, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, 200031, Shanghai, China

    YinXia Zhao

  4. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    Malayannan Subramaniam & Thomas C. Spelsberg

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  1. Jie Yang
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  11. Lie Wang
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  12. Wei Xu
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Contributions

M.L. designed the study, analyzed the data and wrote the manuscript. J.Y., H.K.Z., X.L.W., Y.H.S. and Y.L. performed the experiments. J.G., L.W. and Y.X.Z. revised the paper. W.X., L.W., M.S., and T.C.S. supervised the study and reviewed the paper. All authors read and approved the final version of the paper.

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Correspondence to Lie Wang, Wei Xu or Min Li.

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Yang, J., Zhang, H., Wang, X. et al. Kruppel-like factor 10 protects against acute viral myocarditis by negatively regulating cardiac MCP-1 expression. Cell Mol Immunol 18, 2236–2248 (2021). https://doi.org/10.1038/s41423-020-00539-x

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  • DOI: https://doi.org/10.1038/s41423-020-00539-x

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