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bioRxiv · 10.1101/373670

Novel platelet-neutrophil interaction via activated αIIbβ3 mediates NETosis under flow

Constantinescu-Bercu, A.·Salles-Crawley, I. I.·Woollard, K. J.·Crawley, J. T.
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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 Ib-dependent platelet priming induces integrin IIb{beta}3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet 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 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 cross-talk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.\n\nSummaryPlatelets that are primed following interaction with von Willebrand factor under flow mediated direct interactions with neutrophils via activated platelet integrin, IIb{beta}3, and SLC44A2 on neutrophils. This interaction initiates signaling in a mechanosensitive manner that promotes neutrophil extracellular trap formation.

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Constantinescu-Bercu, A., Salles-Crawley, I. I., Woollard, K. J., Crawley, J. T.. 2018-07-21. Novel platelet-neutrophil interaction via activated αIIbβ3 mediates NETosis under flow. https://doi.org/10.1101/373670

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