title: Receptor for Advanced Glycation End Products (RAGE) Serves a Protective Role during Klebsiella pneumoniae - Induced Pneumonia.
abstract: Klebsiella species is the second most commonly isolated gram-negative organism in sepsis and a frequent causative pathogen in pneumonia. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory responses. We here aimed to investigate the role of RAGE in the host response to Klebsiella (K.) pneumoniae pneumonia and intransally inoculated rage gene deficient (RAGE-/-) and normal wild-type (Wt) mice with K. pneumoniae. Klebsiella pneumonia resulted in an increased pulmonary expression of RAGE. Furthermore, the high-affinity RAGE ligand high mobility group box-1 was upregulated during K. pneumoniae pneumonia. RAGE deficiency impaired host defense as reflected by a worsened survival, increased bacterial outgrowth and dissemination in RAGE-/- mice. RAGE-/- neutrophils showed a diminished phagocytosing capacity of live K. pneumoniae in vitro. Relative to Wt mice, RAGE-/- mice demonstrated similar lung inflammation, and slightly elevated-if any-cytokine and chemokine levels and unchanged hepatocellular injury. In addition, RAGE-/- mice displayed an unaltered response to intranasally instilled Klebsiella lipopolysaccharide (LPS) with respect to pulmonary cell recruitment and local release of cytokines and chemokines. These data suggest that (endogenous) RAGE protects against K. pneumoniae pneumonia. Also, they demonstrate that RAGE contributes to an effective antibacterial defense during K. pneumoniae pneumonia, at least partly via its participation in the phagocytic properties of professional granulocytes. Additionally, our results indicate that RAGE is not essential for the induction of a local and systemic inflammatory response to either intact Klebsiella or Klebsiella LPS.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Achouiti
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.affiliation: Department of Internal Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Department of Internal Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, North Shore Long Island University Hospital, Manhassat, New York, United States of America.|Division of Internal Medicine and Infectious Diseases, University Medical Center of Utrecht, Utrecht, the Netherlands.|Laboratory of Translational Immunology (LTI), University Medical Center of Utrecht, Utrecht, the Netherlands.
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007710:Klebsiella Infections / Q000235:genetics / Q000378:metabolism*; D007711:Klebsiella pneumoniae; D008168:Lung / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D000067759:Receptor for Advanced Glycation End Products
references.citation: Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 2):S5-11
references.pmid: 10556161
references.citation: Am J Respir Crit Care Med. 2013 Jun 15;187(12):1324-34
references.pmid: 23611140
references.citation: J Clin Invest. 2002 Mar;109(6):699-705
references.pmid: 11901175
references.citation: Am J Respir Crit Care Med. 2002 May 15;165(10):1445-50
references.pmid: 12016110
references.citation: Am J Respir Crit Care Med. 2003 Jan 15;167(2):171-9
references.pmid: 12406830
references.citation: Curr Opin Infect Dis. 2003 Jun;16(3):193-8
references.pmid: 12821807
references.citation: J Exp Med. 2003 Nov 17;198(10):1507-15
references.pmid: 14623906
references.citation: Trends Immunol. 2003 Dec;24(12):622-4
references.pmid: 14644132
references.citation: Blood. 2004 Mar 1;103(5):1702-9
references.pmid: 14592828
references.citation: Mol Cell Biol. 2004 Jun;24(11):4880-94
references.pmid: 15143181
references.citation: J Clin Invest. 2004 Jun;113(11):1641-50
references.pmid: 15173891
references.citation: N Engl J Med. 1995 Dec 14;333(24):1618-24
references.pmid: 7477199
references.citation: Clin Microbiol Rev. 1998 Oct;11(4):589-603
references.pmid: 9767057
references.citation: Lancet. 1998 Oct 17;352(9136):1295-302
references.pmid: 9788476
references.citation: J Biol Chem. 1999 Jul 9;274(28):19919-24
references.pmid: 10391939
references.citation: Science. 1999 Jul 9;285(5425):248-51
references.pmid: 10398600
references.citation: Am J Respir Crit Care Med. 2004 Dec 15;170(12):1310-6
references.pmid: 15374839
references.citation: Crit Care Med. 2005 Mar;33(3):564-73
references.pmid: 15753748
references.citation: Clin Microbiol Infect. 2005 Jul;11 Suppl 4:1-16
references.pmid: 15953019
references.citation: Mod Pathol. 2005 Oct;18(10):1385-96
references.pmid: 15933755
references.citation: Chest. 2005 Oct;128(4):2706-13
references.pmid: 16236946
references.citation: Shock. 2005 Dec;24 Suppl 1:12-8
references.pmid: 16374367
references.citation: Am J Respir Crit Care Med. 2006 May 1;173(9):1008-15
references.pmid: 16456142
references.citation: Crit Care Med. 2006 Oct;34(10):2588-95
references.pmid: 16915117
references.citation: Mod Pathol. 2006 Nov;19(11):1437-45
references.pmid: 16941014
references.citation: J Leukoc Biol. 2007 Jan;81(1):1-5
references.pmid: 17032697
references.citation: J Biol Chem. 2007 Feb 9;282(6):4218-31
references.pmid: 17158877
references.citation: J Immunol. 2007 Feb 15;178(4):2483-90
references.pmid: 17277156
references.citation: Blood. 2007 Feb 15;109(4):1593-601
references.pmid: 17032919
references.citation: Crit Care Med. 2007 May;35(5):1369-75
references.pmid: 17414728
references.citation: Crit Care Med. 2007 Dec;35(12):2799-804
references.pmid: 17901841
references.citation: Crit Care. 2007;11(6):R122
references.pmid: 18042296
references.citation: J Immunol. 2008 Mar 1;180(5):3478-84
references.pmid: 18292574
references.citation: Shock. 2008 Apr;29(4):441-5
references.pmid: 18344842
references.citation: PLoS One. 2008;3(10):e3494
references.pmid: 18946505
references.citation: J Immunol. 2009 Apr 1;182(7):4349-56
references.pmid: 19299735
references.citation: J Infect Dis. 2009 Sep 1;200(5):765-73
references.pmid: 19627249
references.citation: Virology. 2009 Sep 1;391(2):265-73
references.pmid: 19592063
references.citation: Acta Med Okayama. 2009 Aug;63(4):203-11
references.pmid: 19727205
references.citation: Crit Care Med. 2010 Jun;38(6):1414-22
references.pmid: 20386310
references.citation: J Cell Biochem. 2010 Jun 1;110(3):645-59
references.pmid: 20512925
references.citation: Eur Respir J. 2010 Dec;36(6):1337-45
references.pmid: 20378602
references.citation: J Infect. 2011 Jan;62(1):26-33
references.pmid: 21056057
references.citation: J Immunol. 2011 Mar 1;186(5):3248-57
references.pmid: 21270403
references.citation: Shock. 2011 May;35(5):492-8
references.pmid: 21263385
references.citation: J Immunol. 2011 Jun 1;186(11):6191-8
references.pmid: 21502377
references.citation: PLoS One. 2011;6(5):e20132
references.pmid: 21629785
references.citation: Crit Care. 2011;15(2):208
references.pmid: 21457506
references.citation: Curr Opin Infect Dis. 2012 Jun;25(3):304-11
references.pmid: 22327468
references.citation: Genesis. 2001 May;30(1):36-44
references.pmid: 11353516