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, 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.
van Zoelen
Marieke A D
MA
Center for Infection and Immunity Amsterdam, Germany. M.A.vanZoelen@amc.uva.nl
Schouten
Marcel
M
de Vos
Alex F
AF
Florquin
Sandrine
S
Meijers
Joost C M
JC
Nawroth
Peter P
PP
Bierhaus
Angelika
A
van der Poll
Tom
T
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000254:growth & development
D018925:Chemokines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic