A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance

In this study, we investigated (1) the specific importance of N- vs O-linked sialic acid in protecting against VWF clearance and (2) whether additional receptors contribute to the reduced half-life of hyposialylated VWF. α2-3-linked sialic acid accounts for <20% of total sialic acid and is predominantly expressed on VWF O-glycans. Nevertheless, specific digestion with α2-3 neuraminidase (α2-3Neu-VWF) was sufficient to cause markedly enhanced VWF clearance. Interestingly, in vivo clearance experiments in dual VWF–/–/Asgr1–/– mice demonstrated enhanced clearance of α2-3Neu-VWF even in the absence of the AMR. The macrophage galactose-type lectin (MGL) is a C-type lectin that binds to glycoproteins expressing terminal N-acetylgalactosamine or galactose residues. Importantly, the markedly enhanced clearance of hyposialylated VWF in VWF–/–/Asgr1–/– mice was significantly attenuated in the presence of an anti-MGL inhibitory antibody. Furthermore, dose-dependent binding of human VWF to purified recombinant human MGL was confirmed using surface plasmon resonance. Additionally, plasma VWF:Ag levels were significantly elevated in MGL1–/– mice compared with controls. Collectively, these findings identify MGL as a novel macrophage receptor for VWF that significantly contributes to the clearance of both wild-type and hyposialylated VWF.

Source: Blood - February 22, 2018 Category: Hematology Authors: Ward, S. E., OSullivan, J. M., Drakeford, C., Aguila, S., Jondle, C. N., Sharma, J., Fallon, P. G., Brophy, T. M., Preston, R. J. S., Smyth, P., Sheils, O., Chion, A., ODonnell, J. S. Tags: Thrombosis and Hemostasis, Brief Reports Source Type: research