Exosomes Derived From Hypertrophic Cardiomyocytes Induce Inflammation in Macrophages via miR-155 Mediated MAPK Pathway.

Hui Yu,Yunzhi Peng,Zhanli Wang,Wenhui Bai,Lei Qin

doi:10.3389/fimmu.2020.606045

Abstract

The inflammatory immune microenvironment plays an important role in the development of cardiac hypertrophy. Exosomes have emerged as the potent modulators of inflammatory responses. This study aimed to determine how exosomes derived from angiotensin II (Ang II)-induced hypertrophic cardiomyocytes (HCs) interfere with the inflammatory signal pathways in macrophages. Herein, we showed that increased exosome release was observed in HCs when compared to normal cardiomyocytes (NCs). Incubation of the murine macrophage cell line RAW264.7 in the presence of exosomes isolated from the culture media of HCs triggers the secretion of inflammatory cytokines interleukin (IL)-6 and IL-8. Cytokines release induced by HCs-derived exosomes was prevented by down-regulation of Argonaute2 (AGO2), suggesting that the non-coding RNAs were involved in exosome-induced inflammatory responses in RAW 264.7 macrophages. RNA sequencing assays further demonstrated that a total of seven microRNAs were differentially expressed between NCs-derived and HCs-derived exosomes. Importantly, miR-155 played a crucial role in the initiation of inflammation in macrophages. Further analyses demonstrated that HCs-derived exosomes induced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 via miR-155. Our results support the concept that exosomal microRNAs have emerged as important inflammatory response modulators regulating cardiac hypertrophy.

Highlights

Cardiac hypertrophy is commonly observed in some patients with cardiac disease such as congestive heart failure, valve disease, and hypertension [1]
We investigated if the release of exosomes from hypertrophic cardiomyocytes (HCs) can affect the proinflammatory signal transduction pathways in macrophages
Our results suggest that exosome-mediated transfer of miRNAs constitute a novel communication mode between cardiomyocytes and macrophages, indicating a potential role in novel treatments of cardiac hypertrophy

Summary

Introduction

Cardiac hypertrophy is commonly observed in some patients with cardiac disease such as congestive heart failure, valve disease, and hypertension [1]. The dominant response of the heart to almost all forms of hemodynamic overload, myocardial injury, or endocrine disorders will lead to cardiomyocyte hypertrophy [2]. It has been reported that the development of cardiac hypertrophy may be attributed to multiple signaling pathways, such as mTOR, PI3K-Akt, AMPK, and MAPK. Hypertrophic Cardiomyocytes-Derived Exosomes Induce Inflammation [3]. Blocking one or some of the hypertrophic signaling pathways could alleviate the development of cardiac hypertrophy. Exosomes are 30–120 nm endocytic membrane-derived vesicles that are secreted by a variety of different cell types. It is well known that exosomes play significant roles in multiple biological processes including development, cell differentiation, and stress response [4]. Researchers confirmed that exosomes might act as vehicles to deliver cargos to reprogram the cardiac microenvironment, which was believed to contribute to the development of several cardiovascular diseases [6]

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