Exosome derived from CD137-modified endothelial cells regulates the Th17 responses in atherosclerosis.

Liangjie Xu,Jinchuan Yan,Hong Zhou,Tianxin Geng,Li Bo,Guangyao Zang,Yi Liang

doi:10.1111/jcmm.15130

Abstract

The role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137‐modified ECs (CD137‐Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti‐CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137‐Exo efficiently induced the progression of AS in ApoE−/− mice. CD137‐Exo increased the proportion of Th17 cells both in vitro and vivo. The IL‐6 contained in CD137‐Exo which is regulated by Akt and NF‐КB pathway was verified to activate Th17 cell differentiation. IL‐17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1) and E‐selectin in the supernatants of ECs after IL‐17 treatment was dramatically increased. CD137‐Exo promoted the progression of AS and Th17 cell differentiation via NF‐КB pathway mediated IL‐6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS.

Highlights

T helpers 17 (Th17) cells have been identified as a new subset of lymphocytes which are shown to promote atherosclerosis (AS), and their associated cytokines in the pathogenesis of AS appear to be contradictory at first glance.[1-3]
Exosome derived from CD137-modified endothelial cells (ECs) regulated the Th17 cell response in AS development
The expression of IL-6 in exosomes derived from ECs was significantly increased after activation of CD137 signalling, and IL-6 in EC-derived exosomes potentially played an importantly role in AS development by prompting Th17 cell responses through the up-regulation of AKT/ NF-КB signalling

Summary

| INTRODUCTION

T helpers 17 (Th17) cells have been identified as a new subset of lymphocytes which are shown to promote atherosclerosis (AS), and their associated cytokines in the pathogenesis of AS appear to be contradictory at first glance.[1-3]. We investigated exosome-mediated cell-to-cell communication, which induced Th17 cell differentiation and promoted progression of the atherosclerotic plaque. Helped with the ECs-derived exosomes, peripheral inflammation and vascular inflammation are triggered, and the dysfunction of ECs is amplified, promoting atherosclerotic process to the step. Exosomes derived from ECs mediate cell-to-cell communication, and crosstalk between organs further promotes peripheral inflammatory responses, which induces Th17 cell differentiation to promote progression of the atherosclerotic plaque. We hypothesized that the CD137-CD137L signalling induced the formation of atherosclerotic plaque via regulating the Th17 cell responses through modulating EC-derived exosomes. The results showed that CD137-CD137L signalling regulated EC-derived exosomes to induce Th17 cell differentiation through IL-6 and promoted AS progression in ApoE−/− mouse. Our findings implied that EC-derived exosomes could be used as a new cell therapy of AS

| MATERIALS AND METHODS

| DISCUSSION