Limited Role of the Receptor for Advanced Glycation End Products during <b><i>Streptococcus pneumoniae</i></b> Bacteremia

Abstract

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.

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

“…These findings are consistent with cecal ligation and puncture and LPS models of polymicrobial or endotoxic septic shock where RAGE potentiated inflammation and increased mortality (19,36). However, these findings are in contrast to the limited role of RAGE in a model of systemic infection caused by S. pneumoniae where RAGE did not alter multiple metrics of disease severity (21). RAGE is known to directly bind lipopolysaccharide of Gram-negative bacteria (36).…”

“…The finding that RAGE does not alter the course of A. baumannii pneumonia suggests that RAGE may not play a role in the host response to A. baumannii infection. In addition to pneumonia, A. baumannii is a frequent cause of sepsis in humans (28) and RAGE has been implicated in increasing mortality in several murine sepsis (cecal ligation and puncture, Listeria monocytogenes) models (19,20) but does not alter S. pneumoniae systemic infection (21). To determine the impact of RAGE signaling in an A. baumannii model of systemic infection, WT and RAGE Ϫ/Ϫ mice were challenged retro-orbitally with A. baumannii and survival was assessed over time.…”

“…Therefore, a mechanistic understanding of how intact immune functions control these pathogens to prevent or combat infections is essential. RAGE is known to play a key role in inflammation, which is required for the control of many bacterial infections, and yet investigations into the role of this receptor in antibacterial responses have centered on studies of professional pathogens and pathogen-agnostic models of septic shock (16,19,21). Here, we investigated the role for RAGE in infections caused by the important opportunistic pathogen A. baumannii, using murine models of pulmonary and systemic infection.…”

“…RAGE contributed to host defense in a murine model of Klebsiella pneumoniae pneumonia, but loss of RAGE resulted in decreased mortality in a murine model of Streptococcus pneumoniae pneumonia (16)(17)(18). Similarly, RAGE Ϫ/Ϫ mice had reduced mortality in a cecal ligation and puncture model of sepsis, but the loss of RAGE did not alter disease severity in a S. pneumoniae model of sepsis (19)(20)(21). Therefore, RAGE signaling impacts disease severity in a pathogen-specific manner.…”

Myeloid-related protein-14 deficiency promotes inflammation in staphylococcal pneumonia

“…The total pathology score was expressed as the sum of the score for all parameters. Granulocyte staining was done using fluorescein isothiocyanate-labelled rat anti-mouse Ly-6 mAb (Pharmingen, San Diego, CA, USA) as described previously [27]. Ly-6G expression in the lung tissue sections was quantified by digital image analysis [28]; the amount of Ly-6G positivity was expressed as a percentage of the total surface area.…”