The urokinase/urokinase receptor system mediates the IgG immune complex-induced inflammation in lung.
Immune complex (IC) deposition induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by the cell surface-specific receptor (uPAR), a binding partner for the urokinase-type plasminogen activator (uPA). We assessed the role of the uPA/uPAR system in IC-induced inflammation using the pulmonary reverse passive Arthus reaction in mice lacking uPA and uPAR compared with their corresponding wild-type controls. Both uPA-deficient C57BL/6J (uPA(-/-)) and uPAR-deficient mice on a mixed C57BL/6J (75%) x 129 (25%) background (uPAR(-/-)) demonstrated a marked reduction of the inflammatory response due to decreased production of proinflammatory mediators TNF-alpha and Glu-Leu-Arg (ELR)-CXC chemokine MIP-2. In uPAR(-/-) animals, the reduction of inflammatory response was more pronounced because of decreased migratory capacity of polymorphonuclear leukocytes. We show that the uPA/uPAR system is activated in lung of wild-type mice, particularly in resident alveolar macrophages (AM), early in IC-induced alveolitis. This activation is necessary for an adequate C5a anaphylatoxin receptor signaling on AM that, in turn, modulates the functional balance of the activating/inhibitory IgG FcgammaRs responsible for proinflammatory mediator release. These data provide the first evidence that the uPA/uPAR plays an important immunoregulatory role in the initiation of the reverse passive Arthus reaction in the lung by setting the threshold for C5a anaphylatoxin receptor/FcgammaR activation on AM. The findings indicate an important link between the uPA/uPAR system and the two main components involved in the IC inflammation, namely, complement and FcgammaRs.
Shushakova
Nelli
N
Department of Nephrology, Medical School Hannover, Hannover, Germany.
Eden
Gabriele
G
Dangers
Marc
M
Zwirner
Joerg
J
Menne
Jan
J
Gueler
Faikah
F
Luft
Friedrich C
FC
Haller
Hermann
H
Dumler
Inna
I
D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology*; D007105:Immune Complex Diseases / Q000473:pathology; D007074:Immunoglobulin G / Q000276:immunology*; D007249:Inflammation / Q000209:etiology*; D008171:Lung Diseases / Q000473:pathology*; D016676:Macrophages, Alveolar; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000502:physiology; D017452:Receptors, IgG / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000502:physiology*
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; C524899:Plaur protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D055293:Receptors, Urokinase Plasminogen Activator; D010047:Ovalbumin; D014568:Urokinase-Type Plasminogen Activator