Urokinase receptor (CD87) regulates leukocyte recruitment via β2 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 ofleukocytes 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.