lewis-y-antigen and Atherosclerosis

The N-terminal lectin-like domain (domain 1 [D1]) of thrombomodulin (TM) is known to have an anti-inflammatory function. We previously showed that recombinant TM domain 1 (rTMD1) interacts with a carbohydrate molecule, Lewis Y (Le(y)), which is found to be expressed on adhesion molecules and involved in cell adhesion. Here, we tested the effect of rTMD1/Le(y) interaction on leukocyte recruitment in inflammation.. The expression of Le(y) on the surface of human umbilical vein endothelial cells was increased by tumor necrosis factor-α stimulation. Direct binding of rTMD1 to Le(y) on the cell surface was observed. rTMD1 inhibited Le(y)-mediated leukocyte adhesion on the Le(y)-immobilized flow chamber and activated endothelium under a shear flow. The following leukocyte transmigration to endothelium was also reduced by rTMD1 through binding Le(y). In vivo, treatment of rTMD1 reduced leukocyte recruitment to the inflammatory sites in carotid ligation injury and thioglycollate-induced peritonitis. rTMD1 administration in apolipoprotein E-deficient mice effectively suppressed atherosclerotic plaque formation and macrophage infiltration in atherosclerotic lesions. Increased Le(y) expression, as well as administered rTMD1, was observed in inflamed vessels.. rTMD1 suppresses vascular inflammation by inhibiting leukocyte recruitment to endothelium through attenuating Le(y)-mediated adhesion and further protects against atherosclerosis progression. The present study provides a mechanism showing that rTMD1 can inhibit inflammation by binding to its carbohydrate ligand Le(y).

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Carotid Artery Injuries; Cell Adhesion; Cell Line, Tumor; Chemotaxis, Leukocyte; Coculture Techniques; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes, Mononuclear; Lewis Blood Group Antigens; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Plaque, Atherosclerotic; Protein Structure, Tertiary; Recombinant Proteins; Thrombomodulin; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha; Vasculitis