FcγRIIB on liver sinusoidal endothelial cells is essential for antibody-induced GPVI ectodomain shedding in mice.
The activating platelet collagen receptor glycoprotein VI (GPVI) is a promising antithrombotic target because of its central role in arterial thrombosis and its minor relevance for normal hemostasis. The receptor can be specifically targeted by antibodies and irreversibly downregulated in circulating platelets in vivo, resulting in long-term antithrombotic protection in mice. This GPVI immunodepletion predominantly occurs through ectodomain shedding, which is accompanied by a transient drop in peripheral platelet counts. Mechanistic studies on this targeted GPVI loss have been hampered because it cannot be reproduced in isolated platelets in vitro. Here we show that both the transient thrombocytopenia and GPVI ectodomain shedding depend on the Fc portion of the anti-GPVI antibody and its interaction with the inhibitory Fcγ receptor (FcγR)IIB. In wild-type, but not Fcgr2b(-/-) mice, anti-GPVI-opsonized platelets became transiently trapped in the liver followed by the appearance of the soluble GPVI ectodomain in the plasma. Depletion of Kupffer cells neither affected anti-GPVI-induced platelet accumulation nor GPVI shedding, demonstrating that the other major FcγRIIB-expressing cell type, liver sinusoidal endothelial cells, is required for both processes to occur. These results reveal a novel and unexpected function of hepatic FcγRIIB in the targeted downregulation of GPVI in vivo.
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
David
D
Stegner
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
Michael
M
Popp
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
Viola
V
Lorenz
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
Jacqueline K
JK
Wax
Clinical Department of Immunology and Rheumatology, Medical School Hanover, Hanover, Germany.
J Engelbert
JE
Gessner
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
Bernhard
B
Nieswandt
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001792:Blood Platelets / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D013921:Thrombocytopenia / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; C080571:Fc gamma receptor IIB; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI