4.8 Article

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

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ELIFE
卷 9, 期 -, 页码 -

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ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.53353

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  1. British Heart Foundation [FS/15/65/32036, PG/17/22/32868, FS/18/53/33863]

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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 alpha(IIb)beta(3) activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet alpha(IIb)beta(3) 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 alpha(IIb)beta(3) 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.

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