Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques

Bradfield, Paul; Menon, Arjun; Licina, Marijana; Lee, Boris; Fischer, Nicolas; Fish, Richard; Kwak, Brenda; Fisher, Edward A; Imhof, Beat

doi:10.1371/journal.pone.0159679

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Title		Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques
Authors		Bradfield, Paul Menon, Arjun Licina, Marijana Lee, Boris Fischer, Nicolas Fish, Richard Kwak, Brenda Fisher, Edward A Imhof, Beat show all authors [1 - 9]
Published in		PLOS ONE. 2016, vol. 11, no. 7, p. e0159679
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.
Identifiers		DOI: 10.1371/journal.pone.0159679 PMID: 27442505
Full text		Article (Published version) (10.2 MB) - Free access
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research groups		Molécules d'adhésion et processus de migration cellulaire (167) L'athérosclérose (665)
Citation (ISO format)		BRADFIELD, Paul et al. Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques. In: PLOS ONE, 2016, vol. 11, n° 7, p. e0159679. doi: 10.1371/journal.pone.0159679 https://archive-ouverte.unige.ch/unige:94311