Urokinase-deficient and urokinase receptor-deficient mice have impaired neutrophil antimicrobial activation in vitro.
Leukocytes 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. Neutrophil 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.
Gyetko
Margaret R
MR
Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, 3916 Taubman Center Medical Center Drive, Ann Arbor, MI 48109-0360, USA. mgyetko@umich.edu
Aizenberg
David
D
Mayo-Bond
Laura
L
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D010585:Phagocyte Bactericidal Dysfunction / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D013481:Superoxides / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics
C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D013481:Superoxides; D014568:Urokinase-Type Plasminogen Activator