Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo.
The urokinase receptor (CD87; uPAR) is found in close association with beta 2 integrins on leukocytes. We studied the functional consequence of this association for leukocyte adhesion and migration. In vivo, the beta 2 integrin-dependent recruitment of leukocytes to the inflamed peritoneum of uPAR-deficient mice was significantly reduced as compared with wild-type animals. In vitro, beta 2 integrin-mediated adhesion of leukocytes to endothelium was lost upon removal of uPAR from the leukocyte surface by phosphatidyl-inositol-specific phospholipase C. Leukocyte adhesion was reconstituted when soluble intact uPAR, but not a truncated form lacking the uPA-binding domain, was allowed to reassociate with the cell surface. uPAR ligation with a monoclonal antibody induced adhesion of monocytic cells and neutrophils to vascular endothelium by six- to eightfold, whereas ligation with inactivated uPA significantly reduced cell-to-cell adhesion irrespective of the beta 2 integrin-stimulating pathway. These data indicate that beta 2 integrin-mediated leukocyte-endothelial cell interactions and recruitment to inflamed areas require the presence of uPAR and define a new phenotype for uPAR-deficient mice. Moreover, uPAR ligation differentially modulates leukocyte adhesion to endothelium and provides novel targets for therapeutic strategies in inflammation-related vascular pathologies.
May
A E
AE
Haemostasis Research Unit, Max-Planck Institute, Kerckhoff-Klinik, D-61231 Bad Nauheim, Germany.
Kanse
S M
SM
Lund
L R
LR
Gisler
R H
RH
Imhof
B A
BA
Preissner
K T
KT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018821:CD18 Antigens / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000276:immunology; D010960:Plasminogen Activators / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator