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J Innate Immun. 2013;5(6):603-12. doi: 10.1159/000348739. Epub 2013 Jun 15.

Limited role of the receptor for advanced glycation end products during Streptococcus pneumoniae bacteremia.

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Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.


Streptococcus pneumoniae is one of the most common causes of sepsis. Sepsis is associated with the release of 'damage-associated molecular patterns' (DAMPs). The receptor for advanced glycation end products (RAGE) is a multiligand receptor, abundantly expressed in the lungs, that recognizes several of these DAMPs. Triggering of RAGE leads to activation of the NF-κB pathway and perpetuation of inflammation. Earlier investigations have shown that the absence of RAGE reduces inflammation and bacterial dissemination and increases survival in sepsis caused by S. pneumoniae pneumonia. We hypothesized that the detrimental role of RAGE depends on the level of RAGE expression in the primary organ of infection. By directly injecting S. pneumoniae intravenously, thereby circumventing the extensive RAGE-expressing lung, we here determined whether RAGE contributes to an adverse outcome of bacteremia or whether its role is restricted to primary lung infection. During late-stage infection (48 h), rage(-/-) mice had an attenuated systemic inflammatory response, as reflected by lower plasma levels of proinflammatory cytokines, reduced endothelial cell activation (as measured by E-selectin levels) and less neutrophil accumulation in lung tissue. However, RAGE deficiency did not influence bacterial loads or survival in this model. In accordance, plasma markers for cell injury were similar in both mouse strains. These results demonstrate that while RAGE plays a harmful part in S. pneumoniae sepsis originating from the respiratory tract, this receptor has a limited role in the outcome of primary bloodstream infection by this pathogen.

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