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Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, MI 48109
Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). Evidence in vitro has implicated uPAR as a modulator of ß2 integrin function, particularly CR3 (CD11b/CD18, Mac-1). Pseudomonas aeruginosa infection has been demonstrated to recruit neutrophils to the pulmonary parenchyma by a ß2 integrin-dependent mechanism. We demonstrate that mice deficient in uPAR (uPAR-/-) have profoundly diminished neutrophil recruitment in response to P. aeruginosa pneumonia compared with wild-type (WT) mice. The requirement for uPAR in neutrophil recruitment is independent of the serine protease uPA, as neutrophil recruitment 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 neutrophil recruitment to the lung when an anti-CD11b mAb is given before inoculation with the pathogen, while recruitment of uPAR-/- neutrophils is unaffected. We conclude that uPAR is required for the recruitment of neutrophils to the lung in response to P. aeruginosa pneumonia and that this requirement is independent of uPA. Further, we show that uPAR and CR3 act by a common mechanism during neutrophil recruitment to the lung in response to P. aeruginosa. This is the first report of a requirement for uPAR during cellular recruitment in vivo against a clinically relevant pathogen.
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Y. Xia, G. Borland, J. Huang, I. F. Mizukami, H. R. Petty, R. F. Todd III, and G. D. Ross Function of the Lectin Domain of Mac-1/Complement Receptor Type 3 (CD11b/CD18) in Regulating Neutrophil Adhesion J. Immunol., December 1, 2002; 169(11): 6417 - 6426. [Abstract] [Full Text] [PDF]
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A. E. May, R. Schmidt, S. M. Kanse, T. Chavakis, R. W. Stephens, A. Schomig, K. T. Preissner, and F.-J. Neumann Urokinase receptor surface expression regulates monocyte adhesion in acute myocardial infarction Blood, November 15, 2002; 100(10): 3611 - 3617. [Abstract] [Full Text] [PDF]
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A. W. Rijneveld, M. Levi, S. Florquin, P. Speelman, P. Carmeliet, and T. van der Poll Urokinase Receptor Is Necessary for Adequate Host Defense Against Pneumococcal Pneumonia J. Immunol., April 1, 2002; 168(7): 3507 - 3511. [Abstract] [Full Text] [PDF]
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S. Suzuki, M. Kobayashi, K. Chiba, I. Horiuchi, J. Wang, T. Kondoh, S. Hashino, J. Tanaka, M. Hosokawa, and M. Asaka Autocrine production of epithelial cell-derived neutrophil attractant-78 induced by granulocyte colony-stimulating factor in neutrophils Blood, March 1, 2002; 99(5): 1863 - 1865. [Abstract] [Full Text] [PDF]
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M. R. Gyetko, S. Sud, J. Sonstein, T. Polak, A. Sud, and J. L. Curtis Cutting Edge: Antigen-Driven Lymphocyte Recruitment to the Lung Is Diminished in the Absence of Urokinase-Type Plasminogen Activator (uPA) Receptor, but Is Independent of uPA J. Immunol., November 15, 2001; 167(10): 5539 - 5542. [Abstract] [Full Text] [PDF]
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J.-i. Nishimura, K. L. Phillips, R. E. Ware, S. Hall, L. Wilson, T. L. Gentry, T. A. Howard, Y. Murakami, M. Shibano, T. Machii, et al. Efficient retrovirus-mediated PIG-A gene transfer and stable restoration of GPI-anchored protein expression in cells with the PNH phenotype Blood, May 15, 2001; 97(10): 3004 - 3010. [Abstract] [Full Text] [PDF]
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L. Kjoller and A. Hall Rac Mediates Cytoskeletal Rearrangements and Increased Cell Motility Induced by Urokinase-Type Plasminogen Activator Receptor Binding to Vitronectin J. Cell Biol., March 19, 2001; 152(6): 1145 - 1158. [Abstract] [Full Text] [PDF]
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 M. Resnati, I. Pallavicini, J. M. Wang, J. Oppenheim, C. N. Serhan, M. Romano, and F. Blasi The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R PNAS, February 5, 2002; 99(3): 1359 - 1364. [Abstract] [Full Text] [PDF]
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