Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium - Inhibition by soluble JAM-A

Objective - The junctional adhesion molecule ( JAM)- A on endothelium contributes to the inflammatory recruitment of mononuclear cells involving engagement of its integrin receptor lymphocyte function-associated antigen (LFA)-1. It is unknown whether these functions can be inhibited by soluble forms of JAM-A, whether JAM-A is expressed on atherosclerotic endothelium, and whether it participates in atherogenic recruitment of mononuclear cells. Methods and Results - Adhesion assays revealed that LFA-1-mediated binding of mononuclear cells to intercellular adhesion molecule ( ICAM)- 1 or cytokine-costimulated endothelium was dose-dependently inhibited by soluble JAM-A. Fc (sJAM-A.Fc). Similarly, sJAM-A.Fc reduced stromal cell-derived factor ( SDF)-1 alpha-triggered transendothelial chemotaxis of activated T cells and their SDF-1 alpha-triggered arrest on cytokine-costimulated endothelium under flow conditions. Immunofluorescence analysis revealed an upregulation of JAM-A on early atherosclerotic endothelium of carotid arteries from apolipoprotein E-deficient ( apoE(-/-)) mice fed an atherogenic diet. In ex vivo perfusion assays, pretreatment of mononuclear cells with sJAM-A. Fc inhibited their very late antigen (VLA)-4- independent accumulation on atherosclerotic endothelium of these arteries. Conclusions - Soluble forms of JAM-A can be effectively applied to inhibit distinct steps of mononuclear cell recruitment on inflamed or atherosclerotic endothelium. In conjunction with its expression on atherosclerotic endothelium, this suggests a functional contribution of JAM-A to atherogenesis.