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Blood. 2018 Feb 22;131(8):911-916. doi: 10.1182/blood-2017-06-787853. Epub 2017 Dec 27.

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

Author information

1
Irish Centre for Vascular Biology, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
2
Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND.
3
Inflammation and Immunity Research Group, Trinity Translational Medicine Institute, and.
4
Department of Histopathology, Trinity Translational Medicine Institute, Trinity College Dublin, St. James's Hospital, Dublin, Ireland; and.
5
National Centre for Coagulation Disorders, St. James's Hospital, Dublin, Ireland.

Abstract

Previous studies have shown that loss of terminal sialic acid causes enhanced von Willebrand factor (VWF) clearance through the Ashwell-Morrell receptor (AMR). 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.

Comment in

PMID:
29282218
DOI:
10.1182/blood-2017-06-787853
[Indexed for MEDLINE]

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