Submitted June 26, 2008
Accepted October 24, 2008
CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo
Cyndi Wong, Yong Liu, Jana Yip, Rochna Chand, Janet L Wee, Lisa Oates, Bernhard Nieswandt, Adili Reheman, Heyu Ni, Nicole Beauchemin, and Denise E Jackson*
Immunoreceptor Laboratory, Burnet Institute, Melbourne, Victoria, Australia
Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, Wurzburg, Germany
Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
McGill Cancer Centre, McGill University, Montreal, Quebec, Canada
* Corresponding author; email: djackson{at}burnet.edu.au.
Carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is a surface glycoprotein expressed on various blood cells, epithelial cells and vascular cells. CEACAM1 possesses adhesive and signaling properties mediated by its intrinsic immunoreceptor tyrosine-based inhibitory motifs that recruits SHP-1 protein-tyrosine phosphatase. In this study, we demonstrate that CEACAM1 is expressed on the surface and in intracellular pools of platelets. In addition, CEACAM1 serves to negatively regulate platelet collagen GPVI-FcR gamma chain signaling. Ceacam1-/- platelets displayed enhanced Type I collagen and GPVI-selective ligand, collagen-related peptide, CRP-mediated platelet aggregation, enhanced platelet adhesion on Type I collagen and elevated CRP-mediated alpha and dense granule secretion. Platelets derived from Ceacam1-/- mice form larger thrombi when perfused over a collagen matrix under arterial flow compared to wild-type mice. Furthermore, using intravital microscopy to ferric chloride-injured mesenteric arterioles, we show that thrombi formed in Ceacam1-/- mice were larger and were more stable than wild-type mice in vivo. GPVI depletion using monoclonal antibody JAQ1 treatment of Ceacam1-/- mice showed a reversal in the more stable thrombus growth phenotype. Ceacam1-/- mice were more susceptible Type I collagen induced pulmonary thromboembolism than wild-type mice. Thus, CEACAM1 acts as a negative regulator of platelet-collagen interactions and thrombus growth involving collagen GPVI receptor in vitro and in vivo.
