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Macrophage scavenger receptor SR-AI contributes to the clearance of von Willebrand factor
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Edité par CCSD ; Ferrata Storti Foundation -
International audience. Previously, we identified macrophage-LRP1 as mediating shear stress-dependent clearance of von Willebrand factor (VWF). In control experiments, however, we observed that VWF also binds to macrophages independently of LRP1 under static conditions, suggesting the existence of additional clearance-receptors. In search for such receptors, we focused on the macrophage-specific scavenger-receptor AI (SR-AI). VWF displays efficient binding to SR-AI (half-max binding 14±5 nM). Binding is calcium-dependent and is inhibited by 72±4% in the combined presence of antibodies against the A1-and D4-domains. Association to SR-AI was confirmed in cell-binding experiments using SR-AI-transfected HEK293-cells and THP1derived macrophages. In addition, binding to primary, bone marrow-derived murine SR-AIdeficient macrophages was strongly reduced compared to wild-type murine macrophages. Following expression via hydrodynamic gene transfer, we determined ratios for VWFpropeptide (VWFpp) over VWF-antigen (VWF:Ag), a marker for VWF clearance. VWFpp/VWF:Ag ratios were significantly reduced in SR-AI-deficient mice compared to wildtype mice (0.6±0.2 vs 1.3±0.3; p<0.0001), compatible with a slower clearance of VWF in SR-AI-deficient mice. Interestingly, mutants associated with increased clearance (VWF/p.R1205H and VWF/p.S2179F) had significantly increased binding to purified SR-AI and SR-AI expressed by THP1-derived macrophages. Accordingly, VWFpp/VWF:Ag ratios for these mutants were reduced in SR-AI-deficient mice. In conclusion, we have identified SR-AI as a novel macrophage-specific receptor for VWF. Enhanced binding of VWF mutants to SR-AI may contribute to the increased clearance of these mutants.
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