title: CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo.
abstract: 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 recruit 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 signaling of platelets by collagen through the glycoprotein VI (GPVI)/Fc receptor (FcR)-gamma-chain. ceacam1(-/-) platelets displayed enhanced type I collagen and GPVI-selective ligand, collagen-related peptide (CRP), 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 with wild-type mice. Furthermore, using intravital microscopy to ferric chloride-injured mesenteric arterioles, we show that thrombi formed in vivo in ceacam1(-/-) mice were larger and were more stable than those in wild-type mice. 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 to type I collagen-induced pulmonary thromboembolism than wild-type mice. Thus, CEACAM1 acts as a negative regulator of platelet-collagen interactions and of thrombus growth involving the collagen GPVI receptor in vitro and in vivo.
authors.affiliation: Burnet Institute incorporating the Austin Research Institute, Heidelberg, Australia.
authors.forename: Cyndi
authors.initials: C
authors.lastname: Wong
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jana
authors.initials: J
authors.lastname: Yip
authors.forename: Rochna
authors.initials: R
authors.lastname: Chand
authors.forename: Janet L
authors.initials: JL
authors.lastname: Wee
authors.forename: Lisa
authors.initials: L
authors.lastname: Oates
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Adili
authors.initials: A
authors.lastname: Reheman
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Denise E
authors.initials: DE
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D006410:Hematopoiesis / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054799:Phospholipase C beta / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D010973:Platelet Adhesiveness / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D011655:Pulmonary Embolism / Q000378:metabolism / Q000503:physiopathology; D013927:Thrombosis / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D024042:Collagen Type I; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D054799:Phospholipase C beta; C518037:Plcb2 protein, mouse