AbstractLeukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). We have shown that neutrophil recruitment to the lung during P. aeruginosa pneumonia is impaired in uPAR-deficient (uPAR−/−) mice but is normal in uPA−/− mice. However, both uPA−/− mice and uPAR−/− mice have impaired lung clearance of P. aeruginosa compared with wild-type (WT) mice. To determine the role of uPA and uPAR in antibacterial host defense, we compared neutrophil bacterial-phagocytosis, respiratory burst, and degranulation among uPA−/−, uPAR−/−, and WT mice. Nutrophil phagocytosis was significantly diminished comparing uPA−/− and uPAR−/− mice with WT mice at all time points. The generation of superoxide by both uPA−/− and uPAR−/− neutrophils was about half of that seen in WT neutrophils. Degranulation of azurophilic granules was significantly diminished in uPA−/− neutrophils compared with either uPAR−/− or WT neutrophils. By contrast, agonist-stimulated release of specific granules was not diminished in either uPA−/− or uPAR−/− mice compared with WT. We conclude that the uPA/uPAR system modulates several of the crucial steps in neutrophil activation that result in bacterial killing and effective innate host defense.