van Zoelen Marieke A D, Schouten Marcel, de Vos Alex F, Florquin Sandrine, Meijers Joost C M, Nawroth Peter P, Bierhaus Angelika, van der Poll Tom
Center for Infection and Immunity Amsterdam, Germany.
J Immunol. 2009 Apr 1;182(7):4349-56. doi: 10.4049/jimmunol.0801199.
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways, including NF-kappaB and subsequent transcription of several proinflammatory mediators. To determine the role of RAGE in the innate immune response to S. pneumoniae pneumonia, RAGE-deficient (RAGE(-/-)) and wild-type mice were intranasally inoculated with S. pneumoniae. S. pneumoniae pneumonia resulted in an up-regulation of constitutively present RAGE expression in lung tissue, especially in the interalveolar septae. RAGE(-/-) mice showed an improved survival, which was accompanied by a lower bacterial load in the lungs at 16 h and a decreased dissemination of the bacteria to blood and spleen at 16 and 48 h after inoculation. RAGE(-/-) macrophages showed an improved killing capacity of S. pneumoniae in vitro. Lung inflammation was attenuated in RAGE(-/-) mice at 48 h after inoculation, as indicated by histopathology and cytokine/chemokine levels. Neutrophil migration to the lungs was mitigated in the RAGE(-/-) mice. In addition, in RAGE(-/-) mice, activation of coagulation was diminished. Additional studies examining the effect of RAGE deficiency on the early (6-h) inflammatory response to S. pneumoniae did not reveal an early accelerated or enhanced immune response. These data suggest that RAGE plays a detrimental role in the host response to S. pneumoniae pneumonia by facilitating the bacterial growth and dissemination and concurrently enhancing the pulmonary inflammatory and procoagulant response.
肺炎链球菌是社区获得性肺炎最常见的病因。晚期糖基化终产物受体（RAGE）是一种多配体受体，在肺中广泛表达。RAGE的激活会导致多种细胞内信号通路的活化，包括核因子κB以及随后几种促炎介质的转录。为了确定RAGE在对肺炎链球菌肺炎的固有免疫反应中的作用，将RAGE缺陷型（RAGE(-/-)）小鼠和野生型小鼠经鼻接种肺炎链球菌。肺炎链球菌肺炎导致肺组织中组成性表达的RAGE上调，尤其是在肺泡间隔中。RAGE(-/-)小鼠的存活率提高，接种后16小时肺内细菌载量较低，接种后16小时和48小时细菌向血液和脾脏的播散减少。RAGE(-/-)巨噬细胞在体外对肺炎链球菌的杀伤能力增强。接种后48小时，RAGE(-/-)小鼠的肺部炎症减轻，组织病理学和细胞因子/趋化因子水平表明了这一点。RAGE(-/-)小鼠中中性粒细胞向肺部的迁移减少。此外，在RAGE(-/-)小鼠中，凝血激活减弱。进一步研究RAGE缺陷对肺炎链球菌早期（6小时）炎症反应的影响，未发现早期加速或增强的免疫反应。这些数据表明，RAGE通过促进细菌生长和播散，同时增强肺部炎症和促凝反应，在宿主对肺炎链球菌肺炎的反应中起有害作用。
