Shushakova Nelli, Eden Gabriele, Dangers Marc, Menne Jan, Gueler Faikah, Luft Friedrich C, Haller Hermann, Dumler Inna
Department of Nephrology, Medical School Hannover, Hannover, Germany.
J Immunol. 2005 Sep 15;175(6):4060-8. 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.
免疫复合物（IC）沉积会引发伴有组织损伤的急性炎症反应。IC诱导的炎症由炎症细胞浸润介导，这一过程受到细胞表面特异性受体（uPAR）的高度调控，uPAR是尿激酶型纤溶酶原激活剂（uPA）的结合伴侣。我们通过在缺乏uPA和uPAR的小鼠中使用肺部反向被动Arthus反应，并与相应的野生型对照进行比较，评估了uPA/uPAR系统在IC诱导的炎症中的作用。在混合的C57BL/6J（75%）×129（25%）背景下的uPA缺陷型C57BL/6J（uPA(-/-)）小鼠和uPAR缺陷型小鼠（uPAR(-/-)）均显示，由于促炎介质肿瘤坏死因子-α（TNF-α）和谷氨酸-亮氨酸-精氨酸（ELR）-CXC趋化因子MIP-2的产生减少，炎症反应明显减轻。在uPAR(-/-)动物中，由于多形核白细胞的迁移能力降低，炎症反应的减轻更为明显。我们发现，在IC诱导的肺泡炎早期，野生型小鼠的肺中，特别是在驻留肺泡巨噬细胞（AM）中，uPA/uPAR系统被激活。这种激活对于AM上充分的C5a过敏毒素受体信号传导是必要的，而这反过来又调节了负责促炎介质释放的激活/抑制性IgG FcγR的功能平衡。这些数据首次证明，uPA/uPAR通过设定AM上C5a过敏毒素受体/FcγR激活的阈值，在肺部反向被动Arthus反应的启动中发挥重要的免疫调节作用。这些发现表明uPA/uPAR系统与IC炎症中涉及的两个主要成分，即补体和FcγR之间存在重要联系。
