Am. J. Respir. Cell Mol. Biol., Volume 22, Number 3, March, 2000 316-322

Nonproteolytic Role for the Urokinase Receptor in Cellular Migration In Vivo

David A. Waltz, Ross M. Fujita, Xuiwei Yang, Lisa Natkin, Shaoqiu Zhuo, Craig J. Gerard, Steven Rosenberg, and Harold A. Chapman

Department of Medicine, Children's Hospital; Department of Medicine, Brigham and Women's Hospital; Harvard Medical School, Boston, Massachusetts; and Chiron Corporation, Emeryville, California

The urokinase receptor (uPAR) binds and localizes urokinase activity at cellular surfaces, facilitating fibrinolysis and cellular migration at sites of 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 µg), a potent neutrophil chemoattractant, was delivered to the lungs of wild-type, urokinase-deficient or uPAR-deficient mice 18 h after intraperitoneal injection of 200 µg human immunoglobulin G (IgG) or a fusion protein composed of an amino-terminal receptor-binding fragment of urokinase and a human IgG Fc fragment (GFD-Fc). Whole lung lavage for recovery of leukocytes was performed 4 h later. 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 response. 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 operate in vivo and identify uPAR as a potential target for regulation of inflammatory processes characterized by neutrophil-mediated injury.

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