Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2.
Salles-Crawley, Isabelle I
eLife Sciences Publications, Ltd
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Constantinescu-Bercu, A., Grassi, L., Frontini, M., Salles-Crawley, I. I., Woollard, K., & Crawley, J. T. (2020). Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2.. Elife, 9 https://doi.org/10.7554/eLife.53353
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.
Research Article, Cell Biology, Human Biology and Medicine, VWF, αiibβ3, platelet, neutrophil, SLC44A2, NETosis, Human
British Heart Foundation (FS/15/65/32036)
British Heart Foundation (PG/17/22/32868)
British Heart Foundation (FS/18/53/33863)
External DOI: https://doi.org/10.7554/eLife.53353
This record's URL: https://www.repository.cam.ac.uk/handle/1810/305836
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/