Activated α<sub>IIb</sub>β<sub>3</sub> on platelets mediates flow-dependent NETosis via SLC44A2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32314961.
- Also identified by DOI 10.7554/eLife.53353 and PMC identifier 7253179.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 Ibα-dependent platelet 'priming' induces integrin α<sub>IIb</sub>β<sub>3</sub> activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet α<sub>IIb</sub>β<sub>3</sub> to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in <i>SLC44A2</i> (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 α<sub>IIb</sub>β<sub>3</sub> and VWF-primed platelets. This was confirmed using neutrophils homozygous for the <i>SLC44A2</i> 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 <i>SLC44A2</i> rs2288904-A polymorphism in venous thrombosis.
Medical subject headings
- Extracellular Traps
- Membrane Glycoproteins
- Membrane Transport Proteins
- Neutrophils
- Platelet Activation
- Platelet Glycoprotein GPIIb-IIIa Complex
- Venous Thrombosis