MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy

Xuxia Wei,Xin Sui,Huimin Yi,Xiaomeng Yi,Yang Yang,Guihua Chen,Pinglan Lu,Haijin Lv,Yuling An,Lijuan Li

doi:10.1038/s41419-020-02857-4

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.

Highlights

Acute lung injury (ALI) is a severe inflammatory and damage diseases which can cause respiratory failure and compromised lung function, resulting in a mortality rate over 30%1
We further detected the bronchoalveolar lavage fluid (BALF) protein concentration and found that LPS significantly increased BALF protein concentration, while human umbilical cord mesenchymal stem cells (hucMSCs) reduced BALF protein concentration (Fig. 1b)
The effect of hucMSCs on pulmonary inflammation was determined by ELISA and the results revealed that hucMSCs reversed LPS induced pulmonary inflammation (Fig. 1c)

Summary

Introduction

Acute lung injury (ALI) is a severe inflammatory and damage diseases which can cause respiratory failure and compromised lung function, resulting in a mortality rate over 30%1. Autophagy is a massive degradation pathway that plays key roles in various diseases[2]. Whether autophagy exerts a protective or an active function in ALI remains unclear. A previous study showed that the enhancement of inflammation in mice with autophagy deficient macrophages[3]. Knockdown of two key autophagy initiation proteins (Beclin[1] or Atg5) could reduce clearance and the accumulation of Pseudomonas in infected macrophages[4]. Inhibition of autophagy can augment lipopolysaccharide (LPS)-induced ALI through NF-κB signaling in human bronchial epithelial (HBE) cells[5]. Recent reports indicate that autophagy plays a protective role during the occurrence of ALI. Rapamycin (RAPA, autophagy activator) can induce the clearance of Pseudomonas from

Methods

Results

Conclusion