F11-Receptor (F11R/JAM) Mediates Platelet Adhesion to Endothelial Cells: Role in Inflammatory Thrombosis

Abstract

SummaryThe F11 receptor (F11R) is a cell adhesion molecule (CAM), member of the immunoglobulin superfamily found on the surface of human platelets, and determined to play a role in platelet aggregation, secretion, adhesion and spreading. The same molecule is present also at tight junctions of endothelial cells (EC) where it is known as JAM and acts as a CAM through homophilic interactions. The role of F11R/JAM in the interaction of platelets with endothelial cells was investigated in the current studies. We report here that washed human platelets adhere specifically to a matrix made of immobilized, recombinant sF11R. Furthermore, platelets adhere to cytokine(TNF-α, INF-γ) stimulated human umbilical vein endothelial cells (HUVEC), and approximately 40-60% of the adhesive force is exerted by homophilic interactions between the F11R of platelets and EC. This is evidenced by the inhibition of platelet adhesion to endothelial cells by recombinant soluble form of the F11R, and by two F11R peptides with amino acid sequences of the N-terminal region, and in the 1st Ig fold of the F11R, respectively. This study suggests a role for F11R in the adhesion of platelets to cytokine-inflamed endothelial cells and thus in thrombosis and atherosclerosis induced in non-denuded blood vessels by inflammatory processes. Agents that block the F11R-mediated adhesion of platelets to EC may be of therapeutic value in controlling thrombosis and preventing heart attacks and stroke.

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

“…Interactions between JAM-C on platelets and leukocyte Mac-1 (␣ M ␤ 2 ) may favor the formation of platelet-leukocyte aggregates (36), which may promote the development of atherothrombotic processes (37). In addition, homotypic interactions of JAM-A in trans have been implicated in the adhesion of platelets to inflamed endothelium in flow (38). Thus, JAM-A expressed on circulating platelets may play a role in inflammatory thrombosis or may contribute to the development and progression of atherosclerotic lesions.…”

Junctional adhesion molecules (JAMs): more molecules with dual functions?

“…In addition, homophilic interaction between recombinant soluble JAM-A and native transmembrane JAM-A has been shown biochemically (Bazzoni et al, 2000a). The homophilic interaction can be inhibited by an anti-JAM-A antibody that binds to an epitope close to the N-terminus of the mature protein (Bazzoni et al, 2000a) as well as by a peptide that corresponds to the N-terminal 23 residues of the mature protein (Babinska et al, 2002a). This suggests that the homophilic trans interaction is mediated through the membrane-distal V-type Ig-like domain of JAM-A and that a region at the N-terminus of the molecule is necessary.…”

“…As mentioned above, JAM-A was originally defined as the target of an antibody (F11) that stimulates platelet aggregation (Kornecki et al, 1990;Naik et al, 1995;Wang et al, 1995). Nonstimulated platelets show increased binding to JAM-Atransfected CHO cells compared with mock-transfected CHO cells (Naik et al, 2001); in addition, nonstimulated platelets bind to cytokine (TNF-α or IFN-γ)-stimulated human umbilical vein endothelial cells (HUVEC), and this binding is partially blocked by recombinant soluble JAM-A or JAM-A peptides (Babinska et al, 2002a). These findings suggest that JAM-A could contribute to binding of platelets to activated endothelium.…”

Cis-Dimerization Mediates Function of Junctional Adhesion Molecule A

“…In addition, JAM-A is expressed on the surface of blood cells, including leukocytes and platelets (Gupta et al, 2000). JAM-A has been implicated in a diverse array of functions, including intercellular junction assembly (Liang et al, 2000;Liu et al, 2000), cell adhesion (Mandell et al, 2005), leukocyte transmigration (Martin-Padura et al, 1998;Del Maschio et al, 1999;Ostermann et al, 2002;Corada et al, 2005;Khandoga et al, 2005;Ostermann et al, 2005), platelet activation (Kornecki et al, 1990;Naik et al, 1995;Sobocka et al, 2000;Babinska et al, 2002), and angiogenesis (Naik et al, 2003a,b). Additionally, JAM-A has been shown to be a receptor for reovirus (Barton et al, 2001;Forrest et al, 2003;Prota et al, 2003;Campbell et al, 2005).…”