JAM-A: Adhesion Receptor and Signaling Regulator in Atherosclerosis

Abstract

Purpose of review: Cell-cell adhesion between leukocytes, platelets and endothelial cells plays a critical role in vascular inflammation and thrombus formation. This review aims at providing a comprehensive picture of the contribution of the immunoglobulin superfamily (IgSF) cell adhesion receptor Junctional Adhesion Molecule-A (JAM-A) to the process of atherosclerosis.

Recent findings: Proinflammatory and proatherogenic stimulation of endothelial cells results in redistribution of JAM-A from cell-cell junctions to the apical surface to promote monocyte adhesion and transmigration. Agonist-stimulation of platelets results in elevated surface levels of JAM-A concomitant with enhanced release of soluble JAM-A (sJAM-A). sJAM-A promotes platelet aggregation, thrombus formation, and platelet-monocyte aggregate formation. Elevated levels of sJAM-A correlate with recurrent myocardial infarction. JAM-A is expressed by several cell types implicated in atherogenesis, notably endothelial cells, platelets, and leukocytes. Proinflammatory and proatherogenic stimuli induce a redistribution of JAM-A within endothelial cells. Stimulated platelets release sJAM-A into the circulation. This review illustrates the role of JAM-A in atherogenesis and elaborates the underlying mechanisms.

Keywords: Atherosclerosis; Coronary artery disease; JAM-A; Leukocyte-endothelial cell interaction; Platelet aggregation; Thrombosis.

Fig. 1

Putative function of JAM-A in different cell types during atherogenesis. (A) JAM-A function in endothelial cells. JAM-A is normally localized at interendothelial junctions but is relocalized to the apical membrane domain in response oxLDL and pro-inflammatory cytokines. Apically localized JAM-A interacts with αLβ2 integrin and JAM-A on monocytes. (B) JAM-A function in platelets. JAM-A associates with αIIbβ3 integrin in cis and limits the activity of αIIbβ3 integrin-associated Src kinases through Csk. Soluble JAM-A released from platelets and endothelial cells activates platelet functions including aggregation and αIIbβ3 integrin-mediated binding to fibrinogen. Activated platelets also interact with endothelial cells and endothelial cell-bound monocytes. (C) JAM-A expression in plaque-associated cells. JAM-A is expressed by macrophages in the atherosclerotic plaque. Since JAM-A stimulates macrophage phagocytic activity it might contribute to the formation of foam cells through JAM-A-triggered phagocytosis of platelets. JAM-A expression by smooth muscle cells contributes to plaque formation by regulating smooth muscle cell migration. Abbreviations: Fn, fibrinogen; oxLDL, oxidized low density lipoprotein; sJAM-A, soluble JAM-A; SMC, smooth muscle cell