Activated ?IIb?3 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 Ib?-dependent platelet 'priming' induces integrin ?IIb?3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet ?IIb?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?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.

SUBMITTER: Constantinescu-Bercu A 

PROVIDER: S-EPMC7253179 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature