Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

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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 Iba-dependent platelet 'priming' induces integrin a_IIbb₃ activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet a_IIbb₃ 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 a_IIbb₃andVWF-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.

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All data generated or analysed during this study are included in the manuscript and supporting files. The source data underlying Figs 1, 2, 3, 4, 5c, 6, 8, and Figure 1, 3 and 7 Supplements are provided in separate 'Source Data' files.

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Adela Constantinescu-Bercu

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1274-2867
Luigi Grassi

Department of Haematology, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Mattia Frontini

Department of Haematology, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Isabelle I Salles-Crawley

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

For correspondence
i.salles@imperial.ac.uk

Competing interests
The authors declare that no competing interests exist.
Kevin Woollard

Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

For correspondence
k.woollard@imperial.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9839-5463
James TB Crawley

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

For correspondence
j.crawley@imperial.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6723-7841

Funding

British Heart Foundation (FS/15/65/32036)

Isabelle I Salles-Crawley
Kevin Woollard
James TB Crawley

British Heart Foundation (PG/17/22/32868)

Isabelle I Salles-Crawley
Kevin Woollard
James TB Crawley

British Heart Foundation (FS/18/53/33863)

Mattia Frontini

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Specific ethical approval was obtained from the Imperial College Research Ethics Committee (19IC5523) for drawing blood from healthy volunteers and genotyping these for the SLC44A2 SNP. Fresh blood was collected from consented healthy volunteers.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.