von Willebrand factor promotes leukocyte extravasation.
von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF-specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF-receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for leukocyte extravasation, in agreement with our observation that anti-VWF antibodies did not affect leukocyte rolling and adhesion. Searching for possible effects downstream of leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil extravasation at a step downstream of leukocyte docking to the vessel wall. This step could be related to leukocyte diapedesis facilitated by destabilization of the endothelial barrier.
Petri
Björn
B
Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Broermann
Andre
A
Li
Hang
H
Khandoga
Alexander G
AG
Zarbock
Alexander
A
Krombach
Fritz
F
Goerge
Tobias
T
Schneider
Stefan W
SW
Jones
Claire
C
Nieswandt
Bernhard
B
Wild
Martin K
MK
Vestweber
Dietmar
D
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D002199:Capillary Permeability; D002465:Cell Movement; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D019007:P-Selectin / Q000276:immunology; D010537:Peritoneum / Q000276:immunology; D010538:Peritonitis / Q000276:immunology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology; D014841:von Willebrand Factor / Q000276:immunology*
D000906:Antibodies; D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor