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



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.



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.
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Christopher W
CW
Smith
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Steven G
SG
Thomas
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Zaher
Z
Raslan
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Pushpa
P
Patel
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Maxwell
M
Byrne
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Marie
M
Lordkipanidzé
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Danai
D
Bem
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Linde
L
Meyaard
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Yotis A
YA
Senis
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.).
Steve P
SP
Watson
From the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences (C.W.S., S.G.T., Z.R., P.P., M.B., M.L., Y.A.S., S.P.W., A.M.), and Institute of Applied Health Research, College of Medical and Dental Sciences (D.B.), University of Birmingham, United Kingdom; and Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, the Netherlands (L.M.). a.mazharian@bham.ac.uk.
Alexandra
A
Mazharian
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D002712:Chlorides; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005290:Ferric Compounds; D020022:Genetic Predisposition to Disease; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D017452:Receptors, IgG / Q000097:blood; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013922:Thrombocytosis / Q000097:blood* / Q000235:genetics; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D019061:src-Family Kinases / Q000097:blood
D002352:Carrier Proteins; D002712:Chlorides; D005290:Ferric Compounds; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; D011971:Receptors, Immunologic; C435908:collagen-related peptide; C108073:leukocyte-associated immunoglobulin-like receptor 1; C098341:platelet membrane glycoprotein VI; D019061:src-Family Kinases; C024555:ferric chloride
LAIR-1; immunoreceptor tyrosine-based activation motif; immunoreceptor tyrosine-based inhibition motif; platelet hyperactivity, Src Family Kinase; thrombocytosis