The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity. J Clin Invest 2018 Aug 31;128(9):4057-4073
Date
08/21/2018Pubmed ID
30124466Pubmed Central ID
PMC6118640DOI
10.1172/JCI96400Scopus ID
2-s2.0-85052566583 (requires institutional sign-in at Scopus site) 58 CitationsAbstract
Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.
Author List
Swystun LL, Lai JD, Notley C, Georgescu I, Paine AS, Mewburn J, Nesbitt K, Schledzewski K, Géraud C, Kzhyshkowska J, Goerdt S, Hopman W, Montgomery RR, James PD, Lillicrap DAuthor
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Animals
Cell Adhesion Molecules, Neuronal
Child
Child, Preschool
Drug Combinations
Endocytosis
Endothelial Cells
Factor VIII
Female
Genetic Variation
Half-Life
Humans
Infant
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Protein Binding
Protein Stability
Young Adult
von Willebrand Factor
