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* Center for Infection and Immunity Amsterdam,
Center for Experimental and Molecular Medicine,
Department of Pathology, and
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and
¶ Department of Internal Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
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-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was in part supported by grants from the Deutsche Forschungsgemeinschaft (SFB405 to P.P.N.) and the Dutch Thrombosis Foundation (to M.S.). This work has been performed at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2 Address correspondence and reprint requests to Dr. Marieke A. D. van Zoelen, Academic Medical Center, Room G2-130, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail address: M.A.vanZoelen{at}amc.uva.nl
3 Abbreviations used in this paper: RAGE, receptor for advanced glycation end products; BALF, bronchoalveolar lavage fluid; CLP, cecal ligation and puncture; HMGB1, high mobility group box 1; KC, cytokine-induced neutrophil chemoattractant; MPO, myeloperoxidase; TATc, thrombin-antithrombin complex; Wt, wild type.
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  R. Ramasamy, S. F. Yan, and A. M. Schmidt RAGE: therapeutic target and biomarker of the inflammatory response--the evidence mounts J. Leukoc. Biol., September 1, 2009; 86(3): 505 - 512. [Abstract] [Full Text] [PDF]
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