Nonproteolytic role for the urokinase receptor in cellular migration in vivo

The urokinase receptor (uPAR) binds and localizes urokinase activity at cel lular surfaces, facilitating fibrinolysis and cellular migration at sites o f tissue injury. uPAR also participates in cellular signaling and regulates integrin-dependent adhesion and migration in vitro. We now report evidence that uPAR occupancy regulates cellular migration in vivo in the absence of functional urokinase. Recombinant murine KC (1.5 mu g), a potent neutrophi l chemoattractant, was delivered to the lungs of wild-type, urokinase-defic ient or uPAR-deficient mice 18 h after intraperitoneal injection of 200 mu g human immunoglobulin G (IgG) or a fusion protein composed of an amino-ter minal receptor-binding fragment of urokinase and a human IgG Fc fragment (G FD-Fc). Whole lung lavage for recovery of leukocytes was performed 4 h late r. KC treatment resulted in a 100-fold increase in lavage neutrophils. GFD- Fc injection resulted in > 50% reduction in neutrophil influx in both wild- type and urokinase-deficient animals but had no effect on uPAR -/- mice. A concomitant reduction in alveolar protein leakage but no change in numbers of circulating neutrophils accompanied this attenuated inflammatory respons e. The reduction in neutrophil influx induced by GFD-Fc is thus related to uPAR occupancy and yet not due to disruption of uPAR-mediated proteolysis. These observations verify that protease-independent functions of uPAR opera te in vivo and identify uPAR as a potential target for regulation of inflam matory processes characterized by neutrophil-mediated injury.