Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2
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 aIIbb3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet aIIbb3 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 aIIbb3 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.
Data availability
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.
Article and author information
Author details
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.
Reviewing Editor
- David Ginsburg, Howard Hughes Medical Institute, University of Michigan, United States
Version history
- Received: November 6, 2019
- Accepted: April 20, 2020
- Accepted Manuscript published: April 21, 2020 (version 1)
- Version of Record published: May 27, 2020 (version 2)
Copyright
© 2020, Constantinescu-Bercu et al.
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.
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