Silencing MicroRNA-155 Attenuates Cardiac Injury and Dysfunction in Viral Myocarditis via Promotion of M2 Phenotype Polarization of Macrophages

Yingying Zhang,Xiangmin Wang,Zongsheng Tang,Mengying Zhang,Kun Lv,Yao Zhang,Xueqin Li,Qifeng Suo,Min Zhong

doi:10.1038/srep22613

Yingying Zhang, Xiangmin Wang + Show 7 more

Open Access

https://doi.org/10.1038/srep22613

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Abstract

Macrophage infiltration is a hallmark feature of viral myocarditis. As studies have shown that microRNA-155 regulates the differentiation of macrophages, we aimed to investigate the role of microRNA-155 in VM. We report that silencing microRNA-155 protects mice from coxsackievirus B3 induced myocarditis. We found that microRNA-155 expression was upregulated and localized primarily in heart-infiltrating macrophages and CD4+ T lymphocytes during acute myocarditis. In contrast with wildtype (WT) mice, microRNA-155−/− mice developed attenuated viral myocarditis, which was characterized by decreased cardiac inflammation and decreased intracardiac CD45+ leukocytes. Hearts of microRNA-155−/− mice expressed decreased levels of the IFN-γ and increased levels of the cytokines IL-4 and IL-13. Although total CD4+ and regulatory T cells were unchanged in miR-155−/− spleen proportionally, the activation of T cells and CD4+ T cell proliferation in miR-155−/− mice were significantly decreased. Beyond the acute phase, microRNA-155−/− mice had reduced mortality and improved cardiac function during 5 weeks of follow-up. Moreover, silencing microRNA-155 led to increased levels of alternatively-activated macrophages (M2) and decreased levels of classically-activated macrophages (M1) in the heart. Combined, our studies suggest that microRNA-155 confers susceptibility to viral myocarditis by affecting macrophage polarization, and thus may be a potential therapeutic target for viral myocarditis.

Highlights

CVB3-induced myocarditis had been considered to be CD4+ T lymphocyte–mediated inflammatory heart disease[4,5], accumulating data indicates that macrophages represent the major inflammatory infiltrates and play a pathogenic role in the development of VM
We found that miR-155 expression increased in heart tissue from CVB3 infected mice compared with phosphate-buffered saline (PBS) injected mice (Fig. 1A)
Because CD4+ T cells and macrophages are the key mediators of pathogenesis in VM, we analyzed the expression of miR-155 in heart-infiltrating mononuclear cells

Summary

Introduction

CVB3-induced myocarditis had been considered to be CD4+ T lymphocyte–mediated inflammatory heart disease[4,5], accumulating data indicates that macrophages represent the major inflammatory infiltrates and play a pathogenic role in the development of VM. Our previous study[23] found that M1 macrophages demonstrated greater expression of miR-155 than M2 macrophages, suggesting functional importance for this miRNA in macrophage polarization. Despite these reported functions of miR-155 in both innate and adaptive immune cells, there has been little genetic evidence that endogenously expressed miR-155 impacts inflammatory responses in vivo to date. The present study provides genetic evidence to support a novel role of endogenous miR-155 in modulating macrophage polarization in a pattern that protects mice from CVB3-induced VM

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