Recombinant Lectin-Like Domain of Thrombomodulin Suppresses Vascular Inflammation by Reducing Leukocyte Recruitment via Interacting with Lewis Y on Endothelial Cells
Objective—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 (Ley), which is found to be expressed on adhesion molecules and involved in cell adhesion. Here, we tested the effect of rTMD1–Ley interaction on leukocyte recruitment in inflammation.
Approach and Results—The expression of Ley on the surface of human umbilical vein endothelial cells was increased by tumor necrosis factor-α stimulation. Direct binding of rTMD1 to Ley on the cell surface was observed. rTMD1 inhibited Ley-mediated leukocyte adhesion on the Ley-immobilized flow chamber and activated endothelium under a shear flow. The following leukocyte transmigration to endothelium was also reduced by rTMD1 through binding Ley. 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 Ley expression, as well as administered rTMD1, was observed in inflamed vessels.
Conclusions—rTMD1 suppresses vascular inflammation by inhibiting leukocyte recruitment to endothelium through attenuating Ley-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 Ley.
- Received December 20, 2012.
- Accepted July 26, 2013.
- © 2013 American Heart Association, Inc.