Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection

Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87), Evidence in vitro has implicated uPAR as a modulator of beta(2) integrin function, particularly CR3 (CD11b/CD18, Mac- 1), Pseudomonas aeruginosa infection has been demonstrated to recruit neutr ophils to the pulmonary parenchyma by a beta(2) integrin-dependent mechanis m. We demonstrate that mice deficient in uPAR (uPAR(-/-)) have profoundly d iminished neutrophil recruitment in response to P, aeruginosa pneumonia com pared with wild-type (WT) mice. The requirement for uPAR in neutrophil recr uitment is independent of the serine protease uPA, as neutrophil recruitmen t in uPA(-/-) mice is indistinguishable from recruitment in WT mice. uPAR(- /-) mice have impaired clearance of P, aeruginosa compared with WT mice, as demonstrated by CFU and comparative histology, WT mice have diminished neu trophil recruitment to the lung when an anti-CD11b mAb is given before inoc ulation with the pathogen, while recruitment of uPAR(-/-) neutrophils is un affected. We conclude that uPAR is required for the recruitment of neutroph ils to the lung in response to P, aeruginosa pneumonia and that this requir ement is independent of uPA, Further, we show that uPAR and CR3 act by a co mmon mechanism during neutrophil recruitment to the lung in response to P, aeruginosa. This is the first report of a requirement for uPAR during cellu lar recruitment in vivo against a clinically relevant pathogen.