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Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2.

Constantinescu-Bercu, A; Grassi, L; Frontini, M; Salles-Crawley, II; Woollard, K; Crawley, JT (2020) Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2. Elife, 9. ISSN 2050-084X https://doi.org/10.7554/eLife.53353
SGUL Authors: Salles-Crawley, Isabelle Irene

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Abstract

Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet 'priming' induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.

Item Type: Article
Additional Information: © 2020, Constantinescu-Bercu et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: NETosis, SLC44A2, VWF, cell biology, human, human biology, medicine, neutrophil, platelet, αiibβ3, Blood Platelets, Extracellular Traps, Humans, Membrane Glycoproteins, Membrane Transport Proteins, Neutrophils, Platelet Activation, Platelet Glycoprotein GPIIb-IIIa Complex, Polymorphism, Genetic, Venous Thrombosis, Blood Platelets, Neutrophils, Humans, Venous Thrombosis, Membrane Transport Proteins, Membrane Glycoproteins, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Activation, Polymorphism, Genetic, Extracellular Traps
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Elife
ISSN: 2050-084X
Language: eng
Dates:
DateEvent
27 May 2020Published
21 April 2020Published Online
20 April 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/15/65/32036British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/17/22/32868British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/18/53/33863British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 32314961
Web of Science ID: WOS:000537686500001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114225
Publisher's version: https://doi.org/10.7554/eLife.53353

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