Abstract
Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies.
Highlights
In atherosclerosis, arterial plaque formation is initially triggered by a continued accumulation of normal and modified lipoproteins in the subendothelial layer
We have explored the enigma of monocyte rTEM in-vitro and how this relates to the phenotypic outcome of Junctional Adhesion Molecule C (JAM-C) blockade in-vivo using atherosclerosis as a disease model
We have shown that high and low expression levels of junctional adhesion molecules (JAMs)-C lead to increased rTEM of monocytes
Summary
Arterial plaque formation is initially triggered by a continued accumulation of normal and modified lipoproteins in the subendothelial layer. It is driven by a chronic and maladaptive inflammatory response, wherein tissue resident macrophages derived from monocytes become engorged with cholesterol and persist in the lesion instead of being cleared through emigration or otherwise [1, 2]. Recruitment of monocytes to sites of tissue injury/inflammation and atherosclerotic plaques, is tightly regulated by a series of events involving interactions between adhesion molecules. A major component of the endothelial barrier is the tight junction, which is composed primarily of occludin, claudins and junctional adhesion molecules (JAMs) [6]. The JAM family is composed of the 3 classical members (JAM-A, JAM-B and JAM-C) with a short cytoplasmic tail and 4 nonclassical molecules with a long cytoplasmic tail [6,7,8,9,10]
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