Vascular adhesion protein 1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo.
Granulocyte extravasation from the blood into tissues is a prerequisite for a proper inflammatory response. It is regulated by a multistep adhesion cascade consisting of successive contacts between leukocyte surface receptors and their endothelial ligands on vessels. Vascular adhesion protein 1 (VAP-1) is an endothelial surface glycoprotein with two functions. It is an enzyme (monoamine oxidase) and an adhesion molecule for lymphocytes. Its function in binding of granulocytes or in leukocyte trafficking into sites of inflammation in vivo has remained unknown. Here we show that treatment of rabbits with anti-VAP-1 monoclonal antibodies abrogates approximately 70% of granulocyte extravasation into a site of an experimental inflammation. Using intravital microscopy, VAP-1 blockade is shown to increase the velocity of the rolling granulocytes and the frequency of their jerky skippings during the rolling. In addition, the number of firmly bound leukocytes decreased by 44% when VAP-1 was rendered nonfunctional. Our results suggest that VAP-1 functions as a molecular brake early in the adhesion cascade and consequently decreases the firm adherence; it may also directly influence the transmigration step. These data elucidate a new interplayer in the granulocyte extravasation process and provide a novel physiological function for a member of the monoamine oxidase family.
Tohka
S
S
MediCity Research Laboratory, Turku University and National Public Health Institute, Department in Turku, Turku, Finland.
Laukkanen
M
M
Jalkanen
S
S
Salmi
M
M
D006631:Amine Oxidase (Copper-Containing) / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology*; D002450:Cell Communication; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000502:physiology*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics; D007249:Inflammation; D051379:Mice; D018715:Microscopy, Video; D008995:Monoamine Oxidase / Q000378:metabolism; D010538:Peritonitis / Q000503:physiopathology / Q000517:prevention & control; D011817:Rabbits; D012795:Sialoglycoproteins / Q000502:physiology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D012795:Sialoglycoproteins; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase