Extracellular Vesicles Work as a Functional Inflammatory Mediator Between Vascular Endothelial Cells and Immune Cells

Abstract

Extracellular vesicles (EV) mediated intercellular communication between monocytes and endothelial cells (EC) might play a major role in vascular inflammation and atherosclerotic plaque formation during cardiovascular diseases (CVD). While critical involvement of small (exosomes) and large EV (microvesicles) in CVD has recently been appreciated, the pro- and/or anti-inflammatory impact of a bulk EV (exosomes + microvesicles) on vascular cell function as well as their inflammatory capacity are poorly defined. This study aims to unravel the immunomodulatory content of EV bulk derived from control (uEV) and TNF-α induced inflamed endothelial cells (tEV) and to define their capacity to affect the inflammatory status of recipients monocytes (THP-1) and endothelial cells (HUVEC) in vitro. Here, we show that EV derived from inflamed vascular EC were readily taken up by THP-1 and HUVEC. Human inflammation antibody array together with ELISA revealed that tEV contain a pro-inflammatory profile with chemotactic mediators, including intercellular adhesion molecule (ICAM)-1, CCL-2, IL-6, IL-8, CXCL-10, CCL-5, and TNF-α as compared to uEV. In addition, EV may mediate a selective transfer of functional inflammatory mediators to their target cells and modulate them toward either pro-inflammatory (HUVEC) or anti/pro-inflammatory (THP-1) mode. Accordingly, the expression of pro-inflammatory markers (IL-6, IL-8, and ICAM-1) in tEV-treated HUVEC was increased. In the case of THP-1, EC-EV do induce a mixed of pro- and anti-inflammatory response as indicated by the elevated expression of ICAM-1, CCL-4, CCL-5, and CXCL-10 proteins. At the functional level, EC-EV mediated inflammation and promoted the adhesion and migration of THP-1. Taken together, our findings proved that the EV released from inflamed EC were enriched with a cocktail of inflammatory markers, chemokines, and cytokines which are able to establish a targeted cross-talk between EC and monocytes and reprogramming them toward a pro- or anti-inflammatory phenotypes.

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

“…Previous studies also suggested that, in response to alcohol or lipid exposure, hepatocyte-derived EVs stimulated expression of inflammatory cytokines and chemokines, including IL6, IL-1β, and CXCL10, and induced activation and chemotaxis of Kupffer cells and mouse BMDMs [48][49][50]. A recent study further demonstrated that inflamed endothelial cell-derived EVs mediated selective transfer of inflammatory chemokines and cytokines to target monocytes and reprogramed them toward M1 or M2 phenotypes [51]. Additionally, it has been shown that exosomes derived from alcoholic hepatocytes transferred miRNA-122 to macrophages, increased expression of pro-inflammatory cytokines, and sensitized monocytes to LPS stimulation [52].…”

miR-130a and Tgfβ Content in Extracellular Vesicles Derived from the Serum of Subjects at High Cardiovascular Risk Predicts their In-Vivo Angiogenic Potential

“…functional miRNAs into vascular cells using EVs 15 . Similarly, EVs released from cytokine-induced inflamed ECs impact on both ECs and monocytes, and regulate the vascular inflammatory response via the expression of the intercellular adhesion molecule 1, ICAM-1, and the recruitment of inflammatory cells 16 . Indeed, changes in circulating EV cargo have been associated with endothelial 17 and smooth muscle cell dysfunction in type 2 diabetes (T2DM) 18 .…”

Use of Human Umbilical Vein Endothelial Cells (HUVEC) as a Model to Study Cardiovascular Disease: A Review

“…HUVEC exposed to high glucose concentrations increased EMV production and induced changes in their composition and functionality [162,165], contributing to endothelial dysfunction development and progression. Moreover, TNF-α stimulation of HUVEC caused changes in EVs protein [163,[166][167][168][169], and microRNA expression [168][169][170]. These changes induced functional alterations in the recipient cells, suggesting that EC-derived EVs have a vital mediator role in CV homeostasis [140,[163][164][165][166][167][168][169][170].…”

“…HUVEC have been used to evaluate how different stress conditions affect EVs composition, production, or content, as well as their communication with other endothelial or other cell types [5,[161][162][163][164]]. HUVEC exposed to high glucose concentrations increased EMV production and induced changes in their composition and functionality [162,165], contributing to endothelial dysfunction development and progression.…”