The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/1029/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1029-1037

Articles

Urokinase Receptor (CD87) Regulates Leukocyte Recruitment via β2 Integrins In Vivo

Andreas E. May*, Sandip M. Kanse*, Leif R. Lund{ddagger}, Roland H. Gisler§, Beat A. Imhof||, and Klaus T. Preissner*

From the * Haemostasis Research Unit, Max-Planck Institute, Kerckhoff-Klinik, D-61231 Bad Nauheim, Germany; the {ddagger} Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen, Denmark; the § Basel Institute for Immunology, CH-4001 Basel, Switzerland; and the || Department of Pathology, Centre Medical Universitaire, CH-1211 Geneva 4, Switzerland

The urokinase receptor (CD87; uPAR) is found in close association with β2 integrins on leukocytes. We studied the functional consequence of this association for leukocyte adhesion and migration. In vivo, the β2 integrin–dependent recruitment of leukocytes to the inflamed peritoneum of uPAR-deficient mice was significantly reduced as compared with wild-type animals. In vitro, β2 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 β2 integrin–stimulating pathway. These data indicate that β2 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.

Key Words: leukocyte • endothelial cells • urokinase receptor • β2 integrin • inflammation

Address correspondence to Klaus T. Preissner, Haemostasis Research Unit, Max-Planck-Institute, Kerckhoff-Klinik, Sprudelhof 11, D-61231 Bad Nauheim, Germany. Phone: 49-603-299-6719; Fax: 49-603-299-6707; E-mail: klaus.t.preissner{at}kerckhoff.med.uni-giessen.de

A.E. May was supported by a postdoctoral fellowship grant from the Deutsche Gesellschaft für Kardiologie, Herz- und Kreislaufforschung. Part of this work was supported by a grant (Pr 327/1-3) from the Deutsche Forschungsgemeinschaft and by a grant (no. 31-49241.96) from the Swiss Science Foundation.

Abbreviations used: HUVEC, human umbilical vein endothelial cells; HVSMC, human vascular smooth muscle cells; ICAM-1, intercellular adhesion molecule 1; LFA-1, {alpha}Lβ2 integrin (CD11a/CD18); Mac-1, {alpha}Mβ2 integrin (CD11b/CD18); ns, not significant; piPLC, phosphatidyl-inositol–specific phospholipase C; uPA, urokinase (urinary-type plasminogen activator); uPAR, urokinase receptor.


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