Mice lacking the inhibitory collagen receptor LAIR-1 exhibit a mild thrombocytosis and hyperactive platelets

Objective: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor family. It is an inhibitor of signalling via the immunoreceptor tyrosine-based activation motif (ITAM)-containing collagen receptor complex, GPVI-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 GPVI-specific agonist collagen-related peptide (CRP) despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery following ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signalling downstream of the GPVI-FcRγ-chain and integrin αIIbβ3 in megakaryocytes due to enhanced Src family kinase (SFK) activity.

Conclusions: Findings from this study demonstrate that ablation of LAIR-1 in
megakaryocytes leads to increased SFK activity and downstream signalling 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.