The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia

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, inclu...

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Veröffentlicht in:The Journal of immunology (1950) Jg. 182; H. 7; S. 4349
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.04.2009
Schlagworte:
Animals
Bronchoalveolar Lavage Fluid - cytology
Bronchoalveolar Lavage Fluid - immunology
Chemokines - biosynthesis
Chemokines - immunology
Chemotaxis, Leukocyte - immunology
Inflammation - immunology
Inflammation - microbiology
Inflammation - pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils - immunology
Pneumonia, Pneumococcal - immunology
Pneumonia, Pneumococcal - pathology
Receptor for Advanced Glycation End Products
Receptors, Immunologic - deficiency
Receptors, Immunologic - genetics
Receptors, Immunologic - immunology
Streptococcus pneumoniae - growth & development
ISSN:1550-6606, 1550-6606
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.0801199