The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung

• Published in: The Journal of immunology (1950) 2005-09, Vol.175 (6), p.4060-4068
• Main Authors: Shushakova, Nelli, Eden, Gabriele, Dangers, Marc, Zwirner, Joerg, Menne, Jan, Gueler, Faikah, Luft, Friedrich C, Haller, Hermann, Dumler, Inna
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Antibody Complex - physiology; Immune Complex Diseases - pathology; Immunoglobulin G - immunology; Inflammation - etiology; Lung Diseases - pathology; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Receptor, Anaphylatoxin C5a - metabolism; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - physiology; Receptors, IgG - metabolism; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator - deficiency; Urokinase-Type Plasminogen Activator - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.6.4060

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.