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.
Highlights
Atherosclerosis is a chronic and progressive inflammatory vas cular disorder that largely contributes to the development of cardiovascular diseases (CVD) including coronary artery and peripheral vascular disease [1]
Comparative marker analysis of selected classical (CD9 and CD63) and inflammatory (ICAM-1) asso ciated markers was performed on the bulk of uEV and TNF-α stimulated HUVEC (tEV) using western blot
CD9 (24 kDa), CD63 (30–70 kDa), and intercellular adhesion molecule (ICAM)-1 (90 kDa) were highly enriched in extracellular vesicles (EV) bulk derived from TNF-α stimulated human vascular endothelial cell model (HUVEC) in comparison with EV derived from unstimulated cells (Figure 1B)
Summary
Atherosclerosis is a chronic and progressive inflammatory vas cular disorder that largely contributes to the development of cardiovascular diseases (CVD) including coronary artery and peripheral vascular disease [1]. Regulated inflammatory interactions between two major cellular players, monocytes (MC) and endothelial cells (EC), play a pivotal role in atherosclerotic plaque formation in the arterial intima [2]. Transmigrated MC will initiate the formation of atherosclerotic plaques, termed fatty streaks, in the arterial walls that, in turn, will lead to CVD [7]. We first aim to unravel the immunomodulatory content of EV bulk derived from inflammatory-triggered EC, thereafter, to under stand their pathological and functional impact on the cellular profiles and behavior of recipient cells
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