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

  1. Adela Constantinescu-Bercu
  2. Luigi Grassi
  3. Mattia Frontini
  4. Isabelle I Salles-Crawley  Is a corresponding author
  5. Kevin Woollard  Is a corresponding author
  6. James TB Crawley  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Cambridge, United Kingdom
Research Article
  • Cited 11
  • Views 2,674
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Cite this article as: eLife 2020;9:e53353 doi: 10.7554/eLife.53353
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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 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

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1274-2867
  2. Luigi Grassi

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Mattia Frontini

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9839-5463
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. David Ginsburg, Howard Hughes Medical Institute, University of Michigan, United States

Publication history

  1. Received: November 6, 2019
  2. Accepted: April 20, 2020
  3. Accepted Manuscript published: April 21, 2020 (version 1)
  4. 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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