Exosomal miR-500 Derived From Lipopolysaccharide-Treated Macrophage Accelerates Liver Fibrosis by Suppressing MFN2.

Lisha Chen,Hongbing Yao,Xiangfeng Liu,Zhixi Duan,Yan Huang,Qin Ji,Yu Zhou,Peiqi Huang

doi:10.3389/fcell.2021.716209

Abstract

Liver fibrosis is an outcome of chronic hepatic injury, which can eventually result in cirrhosis, liver failure, and even liver cancer. The activation of hepatic stellate cell (HSC) is a prominent driver of liver fibrosis. Recently, it has been found that the crosstalk between HSCs and immune cells, including hepatic macrophages, plays an important role in the initiation and development of liver fibrosis. As a vital vehicle of intercellular communication, exosomes transfer specific cargos into HSCs from macrophages. Here, we show that exosomes derived from lipopolysaccharide (LPS)-treated macrophages has higher expression level of miR-500. And overexpression or inhibition of miR-500 in macrophage exosomes could promote or suppress HSC proliferation and activation. Treatment of exosomes with miR-500 overexpression can accelerate liver fibrosis in CCl4-induced liver fibrosis mouse model. miR-500 promotes HSC activation and liver fibrosis via suppressing MFN2. Moreover, miR-500 in serum exosomes could be a biomarker for liver fibrosis. Taken together, exosomal miR-500 derived from LPS-activated macrophages promotes HSC proliferation and activation by targeting MFN2 in liver fibrosis.

Highlights

Liver fibrosis is a common pathological outcome of chronic hepatic disease (CHD), which can develop into cirrhosis or hepatocellular carcinoma, furtherly leading into the death (Parsons et al, 2007; Friedman, 2008; Hernandez-Gea and Friedman, 2011; Parola and Pinzani, 2019)
Exosomal miR-223 derived from natural killer cells can inhibit Hepatic stellate cell (HSC) activation by suppressing autophagy (Wang L. et al, 2020); exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells attenuated liver fibrosis by activating autophagy (Qu et al, 2017); exosomal miR-214 from HSCs could regulate CCN2 expression in primary mouse hepatocytes (Chen et al, 2014); fibrogenic signaling is suppressed in HSCs through CCN2 regulating by exosomal miRNA-199a-5p (Chen et al, 2016); in our previous study, we found that exosomes derived from LPS-activated macrophages could be taken up by neighbor HSCs, transferring miR-103-3p to these HSCs. miR-103-3p could promote HSC activation by suppressing Krüppel-like factor 4 (KLF4) (Chen et al, 2020)
We identified a series of dysregulated exosomal miRNAs in LPS-stimulated THP-1 macrophages and found the effects of some exosomal miRNAs on HSC activation in liver fibrosis

Summary

Introduction

Liver fibrosis is a common pathological outcome of chronic hepatic disease (CHD), which can develop into cirrhosis or hepatocellular carcinoma, furtherly leading into the death (Parsons et al, 2007; Friedman, 2008; Hernandez-Gea and Friedman, 2011; Parola and Pinzani, 2019). It may induce the macrophages to develop into M1 type, which produces and releases some cytokines and chemicals, such as TGF-β1 (TGF-β) and IL-6, thereby contributing to HSC activation and liver fibrosis (Fouts et al, 2012)

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