Urokinase receptor (uPAR, CD87) is a platelet receptor important for kinetics and TNF-induced endothelial adhesion in mice

Background-Urokinase plasminogen activator receptor (uPAR, CD87) is a widel y distributed 55-kD, glycoprotein I-anchored surface receptor. On binding o f its ligand uPA, it is known to increase leukocyte adhesion and traffic. U sing genetically deficient mice, we explored the role of uPAR in platelet k inetics and TNF-induced platelet consumption. Methods and Results-Anti-uPAR antibody stained platelets from normal (+/+) but not from uPAR(-/-) mice, as seen by fluorescence-activated cell sorter analysis. Cr-51-labeled platelets from uPAR(-/-) donors survived longer tha n those from +/+ donors when injected into a +/+ recipient. Intratracheal T NF injection induced thrombocytopenia and a platelet pulmonary localization , pronounced in +/+ but absent in uPAR-/- mice. Aprotinin, a plasmin inhibi tor, decreased TNF-induced thrombocytopenia. TNF injection markedly reduced the survival and increased the pulmonary localization of Cr-51-labeled pla telets from +/+ but not from uPAR(-/-) donors, indicating that it is the pl atelet uPAR that is critical for their response to TNF. As seen by electron microscopy, TNF injection increased the number of platelets and polymorpho nuclear neutrophils (PMNs) in the alveolar capillaries of +/+ mice, whereas in uPAR(-/-) mice, platelet trapping was insignificant and PMN trapping wa s slightly reduced. Platelets within alveolar capillaries of TNF-injected m ice were activated, as judged from their shape, and this was evident in +/ but not in uPAR(-/-) mice. Conclusions-These results demonstrate for the first time the critical role of platelet uPAR for kinetics as well as for activation and endothelium adh esion associated with inflammation.