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.

Keywords:
Receptor for advanced glycation end products, Streptococcus pneumoniae, Sepsis
1.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-1310.
2.
Riedemann NC, Guo RF, Ward PA: The enigma of sepsis. J Clin Invest 2003;112:460-467.
3.
Laterre PF, Garber G, Levy H, Wunderink R, Kinasewitz GT, Sollet JP, Maki DG, Bates B, Yan SC, Dhainaut JF: Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med 2005;33:952-961.
4.
van der Poll T, Opal SM: Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet 2009;374:1543-1556.
5.
Christaki E, Lazaridis N, Opal SM: Receptor for advanced glycation end products in bacterial infection: is there a role for immune modulation of receptor for advanced glycation end products in the treatment of sepsis? Curr Opin Infect Dis 2012;25:304-311.
6.
van Zoelen MA, Achouiti A, van der Poll T: The role of receptor for advanced glycation endproducts (RAGE) in infection. Crit Care 2011;15:208.
7.
Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A: Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992;267:14998-15004.
8.
Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao J, Esposito C, Hegarty H, Hurley W, Clauss M, et al: Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem 1992;267:14987-14997.
9.
Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth PP: The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003;198:1507-1515.
10.
Schmidt AM, Yan SD, Yan SF, Stern DM: The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001;108:949-955.
11.
Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP: Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005;83:876-886.
12.
Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grone HJ, Kurschus FC, Schmidt AM, Yan SD, Martin E, Schleicher E, Stern DM, Hammerling GG, Nawroth PP, Arnold B: Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 2004;113:1641-1650.
13.
van Zoelen MA, Schmidt AM, Florquin S, Meijers JC, de BR, de Vos AF, Nawroth PP, Bierhaus A, van der Poll T: Receptor for advanced glycation end products facilitates host defense during Escherichia coli-induced abdominal sepsis in mice. J Infect Dis 2009;200:765-773.
14.
van Zoelen MA, Schouten M, de Vos AF, Florquin S, Meijers JC, Nawroth PP, Bierhaus A, van der Poll T: The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia. J Immunol 2009;182:4349-4356.
15.
Christaki E, Opal SM, Keith JC Jr, Kessimian N, Palardy JE, Parejo NA, Tan XY, Piche-Nicholas N, Tchistiakova L, Vlasuk GP, Shields KM, Feldman JL, Lavallie ER, Arai M, Mounts W, Pittman DD: A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia. Shock 2011;35:492-498.
16.
van Zoelen MA, Achouiti A, Schmidt AM, Yang H, Florquin S, Tracey KJ, van der Poll T: Ligands of the receptor for advanced glycation end products, including high-mobility group box 1, limit bacterial dissemination during Escherichia coli peritonitis. Crit Care Med 2010;38:1414-1422.
17.
Buckley ST, Ehrhardt C: The receptor for advanced glycation end products (RAGE) and the lung. J Biomed Biotechnol 2010;2010:917108.
18.
Lucas R, Verin AD, Black SM, Catravas JD: Regulators of endothelial and epithelial barrier integrity and function in acute lung injury. Biochem Pharmacol 2009;77:1763-1772.
19.
Polizzotto MN, Neo H, Spelman D, Shortt J, Cole-Sinclair MF, Borosak M, Wong P, Wood EM: Streptococcus pneumoniae septicemia associated with red blood cell transfusion. Transfusion 2008;48:1520-1521.
20.
van der Windt GJ, Blok DC, Hoogerwerf JJ, Lammers AJ, de Vos AF, Van't Veer C, Florquin S, Kobayashi KS, Flavell RA, van der Poll T: Interleukin 1 receptor-associated kinase M impairs host defense during pneumococcal pneumonia. J Infect Dis 2012;205:1849-1857.
21.
Wieland CW, van Lieshout MH, Hoogendijk AJ, van der Poll T: Host defence during Klebsiella pneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2. Eur Respir J 2011;37:848-857.
22.
Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010;28:367-388.
23.
Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007;81:1-5.
24.
van Zoelen MA, van der Sluijs KF, Achouiti A, Florquin S, Braun-Pater JM, Yang H, Nawroth PP, Tracey KJ, Bierhaus A, van der Poll T: Receptor for advanced glycation end products is detrimental during influenza A virus pneumonia. Virology 2009;391:265-273.
25.
van Zoelen MA, Wieland CW, van der Windt GJ, Florquin S, Nawroth PP, Bierhaus A, van der Poll T: Receptor for advanced glycation end products is protective during murine tuberculosis. Mol Immunol 2012;52:183-189.
26.
Ramsgaard L, Englert JM, Manni ML, Milutinovic PS, Gefter J, Tobolewski J, Crum L, Coudriet GM, Piganelli J, Zamora R, Vodovotz Y, Enghild JJ, Oury TD: Lack of the receptor for advanced glycation end-products attenuates E. coli pneumonia in mice. PLoS One 2011;6:e20132.
27.
Englert JM, Hanford LE, Kaminski N, Tobolewski JM, Tan RJ, Fattman CL, Ramsgaard L, Richards TJ, Loutaev I, Nawroth PP, Kasper M, Bierhaus A, Oury TD: A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. Am J Pathol 2008;172:583-591.
28.
Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME: A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 2008;22:3716-3727.
29.
Bopp C, Hofer S, Weitz J, Bierhaus A, Nawroth PP, Martin E, Buchler MW, Weigand MA: sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 2008;147:79-83.
30.
Narvaez-Rivera RM, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG: Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis 2012;12:15.
31.
Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA: Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006;173:1008-1015.
32.
Kalea AZ, Reiniger N, Yang H, Arriero M, Schmidt AM, Hudson BI: Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J 2009;23:1766-1774.
33.
Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S, Okamoto H, Shimura S, Karasawa T, Yonekura H, Yamamoto H: Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol 2011;186:3248-3257.
34.
Kurahashi K, Kajikawa O, Sawa T, Ohara M, Gropper MA, Frank DW, Martin TR, Wiener-Kronish JP: Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 1999;104:743-750.
35.
Benacerraf B, Sebestyen MM, Schlossman S: A quantitative study of the kinetics of blood clearance of P32-labelled Escherichia coli and staphylococci by the reticuloendothelial system. J Exp Med 1959;110:27-48.
36.
Lammers AJ, de Porto AP, Florquin S, de Boer OJ, Bootsma HJ, Hermans PW, van der Poll T: Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule. Immunobiology 2011;216:863-870.
37.
Kang YS, Kim JY, Bruening SA, Pack M, Charalambous A, Pritsker A, Moran TM, Loeffler JM, Steinman RM, Park CG: The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen. Proc Natl Acad Sci USA 2004;101:215-220.
38.
Weinberger DM, Harboe ZB, Sanders EA, Ndiritu M, Klugman KP, Ruckinger S, Dagan R, Adegbola R, Cutts F, Johnson HL, O'Brien KL, Scott JA, Lipsitch M: Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis 2010;51:692-699.
39.
Frommhold D, Kamphues A, Hepper I, Pruenster M, Lukic IK, Socher I, Zablotskaya V, Buschmann K, Lange-Sperandio B, Schymeinsky J, Ryschich E, Poeschl J, Kupatt C, Nawroth PP, Moser M, Walzog B, Bierhaus A, Sperandio M: RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo. Blood 2010;116:841-849.
40.
Zen K, Chen CX, Chen YT, Wilton R, Liu Y: Receptor for advanced glycation endproducts mediates neutrophil migration across intestinal epithelium. J Immunol 2007;178:2483-2490.
41.
Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne CM, Gahmberg CG, Bianchi ME, Nawroth PP, Chavakis T: A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 2007;26:1129-1139.
42.
Lebensburger JD, Howard T, Hu Y, Pestina TI, Gao G, Johnson M, Zakharenko SS, Ware RE, Tuomanen EI, Persons DA, Rosch JW: Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin. Blood 2012;119:1915-1921.
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2013
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