Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1).
Polymorphonuclear leukocytes (PMNs) migrate from the blood into areas of inflammation by binding to the endothelial cells of blood vessels via adhesion molecules. Vascular adhesion protein-1 (VAP-1) is one of the molecules mediating leukocyte-endothelial cell interactions. It is also an endothelial cell-surface enzyme (amine oxidase) that produces reactive oxygen species during the catalytic reaction. To study the role of the enzymatic activity of VAP-1 in PMN extravasation, we used an enzymatically inactive VAP-1 mutant, specific amine oxidase inhibitors (including a novel small molecule compound), and anti-VAP-1 antibodies in several flow-dependent models. The enzyme inhibitors diminished PMN rolling on and transmigration through human endothelial cells under conditions of laminar shear stress in vitro. Notably, the enzyme inactivating point mutation abolished the capacity of VAP-1 to mediate transmigration. Moreover, the new VAP-1 inhibitor effectively prevented the extravasation of PMNs in an animal model of inflammation. These data show that the oxidase activity of VAP-1 controls PMN exit from the blood during the relatively poorly understood transmigration step.
Koskinen
Kaisa
K
MediCity Research Laboratory and Department of Medical Microbiology, Turku University. Finland.
Vainio
Petri J
PJ
Smith
David J
DJ
Pihlavisto
Marjo
M
Ylä-Herttuala
Seppo
S
Jalkanen
Sirpa
S
Salmi
Marko
M
D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D036904:Leukocyte Rolling; D008297:Male; D009504:Neutrophils / Q000166:cytology; D010477:Perfusion; D017354:Point Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)