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

Abstract

| 4659 wileyonlinelibrary.com/journal/jcmm 1 | INTRODUC TI ON 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 Recently, growing attention has been paid to the relative contribution of the local vs. peripheral inflammation to the procession of AS. Here, we focused on the communication between peripheral inflammation and vascular inflammation of Th17 cell differentiation during AS.Exosomes are a subset of extracellular vesicles (EVs) released by almost all types of cells, and they play a significant role in cellular proliferation, apoptosis, stress response and differentiation in the initial stage and development of AS. 4,5 In the present study, we investigated exosome-mediated cell-to-cell communication, which induced Th17 cell differentiation and promoted progression of the atherosclerotic plaque. AbstractThe 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. K E Y W O R D S atherosclerosis, endothelial cells; Th17 cells, exosomes

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

“…Additionally, p-Akt and p-eNOS changed synchronously with p-VEGER2. Moreover, our group has demonstrated that the CD137 signaling activated Akt in ECs in atherosclerosis [ 53 ].…”

T helpers 17 cell responses induced cardiac hypertrophy and remodeling in essential hypertension

“…In our previous studies, the Th17 responses amplify the inflammatory responses in arterial wall, and induce the endothelial dysfunction in the atherosclerosis development. Th17-related cytokines greatly contribute to the accumulation of fibrillar exteacelluar matrix (ECM) in atrial fibrillation, and can act as an independent predictor for a higher risk of atrial fibrillation recurrence after catheter ablation [6,7].…”

Hepatocyte-Derived Exosomal microRNAs Orchestrate Vascular Inflammation and Endothelial Function: Insights Into Molecular Mechanisms of Trimethylamine-N-Oxide in Atherosclerosis

“…Particularly, NF-κB signaling pathway has been at the crossroads of in ammation and atherogenesis [33], and speci c NF-κB inhibition of endothelial cell reduced proin ammatory gene expression such as IL-6 and TNF, and protected ApoE -/mice from atherosclerosis [34]. Recent studies have revealed that exosome derived from CD137-modi ed endothelial cells could promote Th17 cell differentiation and atherosclerosis progression in ApoE -/mice through NF-κB pathway mediated IL-6 expression [37], and exosomes released from mature dendritic cells carried TNF-a on exosome membrane, which was found to be e cient in activating the NF-κB pathway, thus provoking endothelial in ammation and atherosclerosis [24]. Furthermore, there exists a close relationship between the NF-κB pathway and the in ammatory cytokines of IL-6, MCP-1 and TNF-α.…”