title: Involvement of a CD47-dependent pathway in platelet adhesion on inflamed vascular endothelium under flow.
abstract: Resting platelet adhesion to inflammatory vascular endothelium is thought to play a causal role in secondary thrombus formation or microcirculatory disturbance after vessel occlusion. However, though adhesion receptors involved in platelet-matrix interactions have been extensively studied, the molecular mechanisms involved in platelet-endothelium interactions are incompletely characterized and have been mainly studied under static conditions. Using human platelets or platelets from wild-type and CD47-/- mice in whole blood, we demonstrated that at low shear rate, CD47 expressed on human and mouse platelets significantly contributes to platelet adhesion on tumor necrosis factor-alpha (TNF-alpha)-stimulated vascular endothelial cells. Using the CD47 agonist peptide 4N1K and blocking monoclonal antibodies (mAbs), we showed that CD47 binds the cell-binding domain (CBD) of endothelial thrombospondin-1 (TSP-1), inducing activation of the platelet alphaIIbbeta3 integrin that in turn becomes able to link the endothelial receptors intercellular adhesion molecule 1 (ICAM-1) and alphavbeta3. Platelet CD36 and GPIbalpha are also involved because platelet incubation with blocking mAbs directed against each of these 2 receptors significantly decreased platelet arrest. Given that anti-CD47 treatment of platelets did not further decrease the adhesion of anti-CD36-treated platelets and CD36 is a TSP-1 receptor, it appears that CD36/TSP-1 interaction could trigger the CD47-dependent pathway. Overall, CD47 antagonists may be potentially useful to inhibit platelet adhesion on inflamed endothelium.
authors.affiliation: Unité Institut National de la Santé et de la Recherche Médicale (INSERM) U343 et Laboratoire d'Immunologie, Nice, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lagadec
authors.forename: Olivier
authors.initials: O
authors.lastname: Dejoux
authors.forename: Michel
authors.initials: M
authors.lastname: Ticchioni
authors.forename: Françoise
authors.initials: F
authors.lastname: Cottrez
authors.forename: Mette
authors.initials: M
authors.lastname: Johansen
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D018955:CD36 Antigens / Q000276:immunology / Q000502:physiology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D004730:Endothelium, Vascular / Q000502:physiology*; D015870:Gene Expression; D018056:Hemorheology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C120273:4N1K peptide; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018955:CD36 Antigens; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1