Activated α < sub > IIb < /sub > β < sub > 3 < /sub > on platelets mediates flow-dependent NETosis via SLC44A2

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 inSLC44A2 (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 aIIbb3andVWF-primed platelets. This was confirmed using neutrophils homozygous for theSLC44A2 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 theSLC44A2 rs2288904-A polymorphism in venous thrombosis.
Source: eLife - Category: Biomedical Science Tags: Cell Biology Human Biology and Medicine Source Type: research