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The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung¹

Nelli Shushakova^*,, Gabriele Eden^*, Marc Dangers^*, Joerg Zwirner, Jan Menne^*,, Faikah Gueler^*, Friedrich C. Luft, Hermann Haller^* and Inna Dumler^2,*,

^* Department of Nephrology, Medical School Hannover, Hannover, Germany; Phenos, Hannover, Germany; Department of Immunology, Georg August University, Goettingen, Germany; and Medical Faculty of the Charité-Franz Volhard Clinic, HELIOS Klinikum-Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany

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- 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 FcRs 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/FcR 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 FcRs.

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The JI 2005 175: 3457-3458. [Full Text]  

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