Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets.

Abstract

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.

• Authors: Christopher W Smith, Steven G Thomas, Zaher Raslan, Pushpa Patel, Maxwell Byrne, Marie Lordkipanidzé, Danai Bem, Linde Meyaard, Yotis A Senis, Steve P Watson, Alexandra Mazharian
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 37 Issue 5 Pg. 823-835 (05 2017) ISSN: 1524-4636 [Electronic] United States
• PMID: 28336561 (Publication Type: Journal Article, Video-Audio Media, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• Carrier Proteins
• Chlorides
• Ferric Compounds
• Peptides
• Platelet Glycoprotein GPIIb-IIIa Complex
• Platelet Membrane Glycoproteins
• Receptors, IgG
• Receptors, Immunologic
• collagen-related peptide
• leukocyte-associated immunoglobulin-like receptor 1
• platelet membrane glycoprotein VI
• src-Family Kinases
• ferric chloride

Topics

• Animals
• Blood Platelets (drug effects, metabolism)
• Carrier Proteins (pharmacology)
• Cells, Cultured
• Chlorides
• Disease Models, Animal
• Enzyme Activation
• Ferric Compounds
• Genetic Predisposition to Disease
• Megakaryocytes (drug effects, metabolism)
• Mice, Knockout
• Peptides (pharmacology)
• Phenotype
• Platelet Activation (drug effects)
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Platelet Membrane Glycoproteins (agonists, metabolism)
• Receptors, IgG (blood)
• Receptors, Immunologic (deficiency, genetics)
• Signal Transduction (drug effects)
• Thrombocytosis (blood, genetics)
• Thrombosis (blood, chemically induced, genetics)
• src-Family Kinases (blood)