Rijneveld Anita W, Levi Marcel, Florquin Sandrine, Speelman Peter, Carmeliet Peter, van Der Poll Tom
Department of Experimental Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands.
J Immunol. 2002 Apr 1;168(7):3507-11. doi: 10.4049/jimmunol.168.7.3507.
Cell recruitment is a multistep process regulated by cytokines, chemokines, and growth factors. Previous work has indicated that the urokinase plasminogen activator receptor (uPAR) may also play a role in this mechanism, presumably by an interaction with the beta(2) integrin CD11b/CD18. Indeed, an essential role of uPAR in neutrophil recruitment during pulmonary infection has been demonstrated for beta(2) integrin-dependent respiratory pathogens. We investigated the role of uPAR and urokinase plasminogen activator (uPA) during pneumonia caused by a beta(2) integrin-independent respiratory pathogen, Streptococcus pneumoniae. uPAR-deficient (uPAR(-/-)), uPA-deficient (uPA(-/-)), and wild-type (Wt) mice were intranasally inoculated with 10(5) CFU S. pneumoniae. uPAR(-/-) mice showed reduced granulocyte accumulation in alveoli and lungs when compared with Wt mice, which was associated with more S. pneumoniae CFU in lungs, enhanced dissemination of the infection, and a reduced survival. In contrast, uPA(-/-) mice showed enhanced host defense, with more neutrophil influx and less pneumococci in the lungs compared with Wt mice. These data suggest that uPAR is necessary for adequate recruitment of neutrophils into the alveoli and lungs during pneumonia caused by S. pneumoniae, a pathogen eliciting a beta(2) integrin-independent inflammatory response. This function is even more pronounced when uPAR is unoccupied by uPA.
细胞募集是一个由细胞因子、趋化因子和生长因子调节的多步骤过程。先前的研究表明，尿激酶型纤溶酶原激活物受体（uPAR）可能也在此机制中发挥作用，推测是通过与β(2)整合素CD11b/CD18相互作用来实现的。事实上，对于依赖β(2)整合素的呼吸道病原体，uPAR在肺部感染期间中性粒细胞募集中的重要作用已得到证实。我们研究了uPAR和尿激酶型纤溶酶原激活物（uPA）在由不依赖β(2)整合素的呼吸道病原体肺炎链球菌引起的肺炎中的作用。将uPAR缺陷型（uPAR(-/-)）、uPA缺陷型（uPA(-/-)）和野生型（Wt）小鼠经鼻接种10(5)CFU肺炎链球菌。与Wt小鼠相比，uPAR(-/-)小鼠肺泡和肺中的粒细胞聚集减少，这与肺中更多的肺炎链球菌CFU、感染的扩散增强以及存活率降低有关。相反，与Wt小鼠相比，uPA(-/-)小鼠表现出更强的宿主防御能力，肺中有更多的中性粒细胞流入且肺炎球菌较少。这些数据表明，在由肺炎链球菌引起的肺炎中，uPAR对于中性粒细胞充分募集到肺泡和肺中是必要的，肺炎链球菌是一种引发不依赖β(2)整合素炎症反应的病原体。当uPAR未被uPA占据时，这种功能更加明显。
