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S.E. Ward et al.
will play a key role in mediating this pathogen-associated enhanced VWF clearance. Interestingly, two previous studies have demonstrated that complete loss of O- linked carbohydrate structures is associated with signifi- cantly increased VWF clearance in vivo.28,55 Given that O- glycans are known to influence protein conformation, the observation that complete removal triggers enhanced clearance is likely attributable to conformational changes in VWF.
In addition to MGL, other macrophage receptors that can also interact with VWF include LRP1, SR-A1, Siglec- 5, Gal-1 and Gal-3.3,56,57 Some of these receptors have also been shown to bind with enhanced affinity to hyposialy- lated VWF (ASGPR, Gal-1 and Gal-3). Additional studies will be necessary to fully elucidate the relative roles of these other macrophage receptors in regulating the phys- iological and/or pathological clearance of hyposialylated VWF. Although it remains unclear whether these recep- tors may function synergistically in regulating desialylat- ed VWF clearance, recent studies have demonstrated that LRP1 can form heterologous functional complexes with other macrophage receptors including β2-integrins. Importantly, Deppermann et al recently demonstrated that MGL on hepatic Küpffer cells plays a significant role in the removal of desialylated platelets, and that MGL and ASGPR appear to function collaboratively in physio- logical platelet clearance.58
Disclosures
JSO’D has served on speakers’ bureaux for Baxter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma, Takeda and Octapharma. He has also served on advisory boards for Baxter, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda and Pfizer and has received research grant funding awards from Baxter, Bayer, Pfizer, Shire, Takeda and Novo Nordisk. JMO’S has received research grant funding from LEO Pharma and Grifols
Contributions
SEW, ABM, JF and AC performed experiments; SEW, JMO’S, ABM, DS, RG, JS, JF, MM, TAJM, AC, SH and JSO’D designed the research and analyzed the data. All authors were involved in writing and reviewing the paper.
Funding
This work was supported by funds from the NIH for the Zimmerman Program (HL081588); a Science Foundation Ireland Principal Investigator Award (11/PI/1066); a Health Research Board Investigator Lead Project Award (ILP-POR- 2017-008) and a National Children’s Research Centre Project Award (C/18/1). ABM is supported by the European Union (GlySign, grant n. 722095)
Data-sharing statement
All original data and protocols can be made available to other investigators upon request.
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