Urokinase Receptor-Deficient Mice Have Impaired Neutrophil Recruitment in Response to PulmonaryPseudomonas aeruginosaInfection

Abstract

Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). Evidence in vitro has implicated uPAR as a modulator of β2 integrin function, particularly CR3 (CD11b/CD18, Mac-1). Pseudomonas aeruginosa infection has been demonstrated to recruit neutrophils to the pulmonary parenchyma by a β2 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.

Sequences within Domain II of the Urokinase Receptor Critical for Differential Ligand Recognition

“…In addition, uPAR is capable of modulating cell adhesion by activating cells directly via a Gprotein-coupled receptor (8), by sequestering caveolin (9), and by affecting intracellular signaling events (10). In support of these in vitro studies, uPAR-deficient mice were found to respond poorly to Pseudomonas aeruginosa infection, because of impaired neutrophil infiltration and reduced monocyte adhesion (11). Clinically, up-regulation of uPAR expression within tumor cells was found to correlate inversely with the survival rate of breast cancer patients (3).…”

Urokinase Induces Basophil Chemotaxis through a Urokinase Receptor Epitope That Is an Endogenous Ligand for Formyl Peptide Receptor-Like 1 and -Like 2

“…uPA also primes neutrophils for superoxide anion release (61), and uPAR expression is required for FMLP-dependent monocyte and granulocyte chemotaxis (45,46) and for neutrophil degranulation (62). Finally, uPA Ϫ/Ϫ and uPAR Ϫ/Ϫ mice show impaired neutrophil recruitment and susceptibility to bacterial infections (12)(13)(14). There is compelling evidence that mast cells and basophils are multifunctional effector cells in inflammation (63) and in host defense against bacteria, viruses and parasites (64).…”

“…Migration of immune cells to tissue lesions is impaired in uPA Ϫ/Ϫ and uPAR Ϫ/Ϫ mice, resulting in impairment of host defenses, bacterial spread, and death (12)(13)(14). Chemotaxis of inflammatory cells stimulated by uPA in vitro and in vivo requires binding to uPAR (15)(16)(17) and the existence of a transmembrane adapter (15,18).…”

Species-specific urokinase receptor ligands reduce glioma growth and increase survival primarily by an antiangiogenesis mechanism

“…Such effects have been seen in a model of chemokine-induced leukocyte migration in uPA-deficient mice. 16 Gyetko et al 56 have observed that uPAR-deficient mice demonstrate impaired recruitment of leukocytes in response to infection and that such an altered response might affect tumor growth. Since leukocyte infiltration of xenotransplanted brain tumors is a very rare occurrence, and we have not observed any such infiltrates in our studies, such a mechanism is unlikely to be responsible for the slower tumor growth in our mice treated with these peptides.…”