title: Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques.
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.
authors.affiliation: Department of Pathology and Immunology, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva 4, Switzerland.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bradfield
authors.affiliation: Division of Cardiology, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Arjun
authors.initials: A
authors.lastname: Menon
authors.affiliation: Department of Pathology and Immunology, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva 4, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Miljkovic-Licina
authors.affiliation: Department of Pathology and Immunology, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva 4, Switzerland.
authors.forename: Boris P
authors.initials: BP
authors.lastname: Lee
authors.affiliation: NovImmune S.A., 14 chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fischer
authors.affiliation: Department of Genetic Medicine and Development, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva, Switzerland.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fish
authors.affiliation: Department of Pathology and Immunology, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva 4, Switzerland.
authors.forename: Brenda
authors.initials: B
authors.lastname: Kwak
authors.affiliation: Division of Cardiology, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Department of Pathology and Immunology, CMU, University of Geneva, 1211, rue Michel Servet 1, Geneva 4, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D062786:Junctional Adhesion Molecule C / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008055:Lipids / Q000097:blood; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D062786:Junctional Adhesion Molecule C; D008055:Lipids