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

Soracha E. Ward, Jamie M. O'Sullivan, Clive Drakeford, Sonia Aguila, Christopher N. Jondle, Jyotika Sharma, Padraic G. Fallon, Teresa M. Brophy, Roger J.S. Preston, Paul Smyth, Orla Sheils, Alain Chion and James S. O'Donnell

Key points

  • VWF sialylation modulates in vivo clearance through Ashwell-Morrell independent pathways.

  • VWF binding to Macrophage Galactose Lectin plays a novel role in facilitating VWF clearance.


Previous studies have shown that loss of terminal sialic acid causes enhanced VWF clearance through the Ashwell-Morrell receptor (AMR). In this study we investigated (i) the specific importance of N- versus O-linked sialic acid in protecting against VWF clearance (ii) 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 to 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.

  • Submitted June 6, 2017.
  • Accepted December 12, 2017.