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Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates

Abstract : Abstract Genome-wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for von Willebrand factor (VWF). To explain the link between Slc44a2 and VT, we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a– or HNA-3b–coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100 s−1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100 s−1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils were preactivated with lipopolysaccharide. Moreover, specific shear conditions with high neutrophil concentration could act as a “second hit,” inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. The fact that neutrophils expressing Slc44a2/HNA-3b have a different response on VWF in the conditions tested could thus explain the association between HNA-3b and a reduced risk for VT in humans.
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Submitted on : Thursday, July 22, 2021 - 12:56:59 AM
Last modification on : Tuesday, October 19, 2021 - 11:00:04 PM




Gaïa Zirka, Philippe Robert, Julia Tilburg, Victoria Tishkova, Chrissta Maracle, et al.. Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates. Blood, American Society of Hematology, 2021, 137 (16), pp.2256-2266. ⟨10.1182/blood.2020008345⟩. ⟨hal-03295352⟩



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