Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets
| Autor: | Linde Meyaard, Marie Lordkipanidzé, Zaher Raslan, Alexandra Mazharian, Pushpa Patel, Steven G. Thomas, Danai Bem, Steve P. Watson, Christopher W Smith, Yotis A. Senis, Maxwell Byrne |
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| Rok vydání: | 2017 |
| Předmět: |
Blood Platelets
0301 basic medicine Platelet Glycoprotein GPIIb-IIIa Complex Platelet Membrane Glycoproteins Biology Ferric Compounds Collagen receptor Immunoreceptor Tyrosine-Based Inhibition Motif 03 medical and health sciences 0302 clinical medicine Chlorides Immunoreceptor tyrosine-based activation motif medicine Animals Genetic Predisposition to Disease Platelet Receptors Immunologic Tyrosine Receptor Cells Cultured Megakaryopoiesis Mice Knockout Thrombocytosis Receptors IgG Thrombosis Platelet Activation medicine.disease Molecular biology Enzyme Activation Disease Models Animal Phenotype src-Family Kinases 030104 developmental biology Biochemistry Carrier Proteins Peptides Cardiology and Cardiovascular Medicine Megakaryocytes Signal Transduction 030215 immunology |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37:823-835 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif–containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif–containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored. In this study, we investigate the role of LAIR-1 in megakaryocyte development and platelet production by generating LAIR-1–deficient mice. Approach and Results— Mice lacking LAIR-1 exhibit a significant increase in platelet counts, a prolonged platelet half-life in vivo, and increased proplatelet formation in vitro. Interestingly, platelets from LAIR-1–deficient mice exhibit an enhanced reactivity to collagen and the glycoprotein VI–specific agonist collagen-related peptide despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery after ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signaling downstream of the glycoprotein VI–FcRγ-chain and integrin αIIbβ3 in megakaryocytes because of enhanced Src family kinase activity. Conclusions— Findings from this study demonstrate that ablation of LAIR-1 in megakaryocytes leads to increased Src family kinase activity and downstream signaling in response to collagen that is transmitted to platelets, rendering them hyper-reactive specifically to agonists that signal through Syk tyrosine kinases, but not to G-protein–coupled receptors. |
| Databáze: | OpenAIRE |
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