title: ATP-binding cassette transporter G1 deficiency dysregulates host defense in the lung.
abstract: BACKGROUND
  Mice with genetic deletion of the cholesterol efflux transporter, ATP-binding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown.
  
  
  OBJECTIVE
  To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms.
  
  
  METHODS
  Abcg1(+/+) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K. pneumoniae, or intraperitoneal LPS. Phenotypic responses were profiled. Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense.
  
  
  RESULTS
  Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(-/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K. pneumoniae were increased in Abcg1(-/-) mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/-) mice had equivalent responses to intravenous K. pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner.
  
  
  CONCLUSIONS
  Abcg1(-/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Draper
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Madenspacher
authors.forename: Darlene
authors.initials: D
authors.lastname: Dixon
authors.forename: Debra H
authors.initials: DH
authors.lastname: King
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D017353:Gene Deletion; D007113:Immunity, Innate; D007711:Klebsiella pneumoniae; D007958:Leukocyte Count; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008074:Lipoproteins / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Mar;284(3):L518-25
references.pmid: 12495943
references.citation: Am J Respir Cell Mol Biol. 2001 Sep;25(3):335-40
references.pmid: 11588011
references.citation: Am J Physiol. 1997 Sep;273(3 Pt 1):L634-9
references.pmid: 9316499
references.citation: J Biol Chem. 2005 Aug 26;280(34):30150-7
references.pmid: 15994327
references.citation: J Immunol. 2003 Jul 15;171(2):955-63
references.pmid: 12847267
references.citation: Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2365-71
references.pmid: 15514210
references.citation: Am Rev Respir Dis. 1986 Dec;134(6):1266-72
references.pmid: 3024539
references.citation: J Immunol. 2008 Mar 1;180(5):3305-12
references.pmid: 18292555
references.citation: J Biol Chem. 2006 Sep 29;281(39):29401-10
references.pmid: 16887795
references.citation: J Clin Invest. 2007 Dec;117(12):3900-8
references.pmid: 17992262
references.citation: Neuropsychobiology. 2000;42 Suppl 1:22-5
references.pmid: 11093066
references.citation: Am J Respir Cell Mol Biol. 2005 Jun;32(6):531-9
references.pmid: 15778492
references.citation: J Immunol. 2008 Mar 1;180(5):3560-8
references.pmid: 18292583
references.citation: J Biol Chem. 2005 Jun 10;280(23):21763-72
references.pmid: 15826936
references.citation: Circulation. 2009 Mar 3;119(8):1135-45
references.pmid: 19221221
references.citation: J Clin Invest. 2008 Nov;118(11):3701-13
references.pmid: 18924609
references.citation: Biochim Biophys Acta. 1996 Aug 13;1290(3):231-40
references.pmid: 8765125
references.citation: Cell Metab. 2005 Feb;1(2):121-31
references.pmid: 16054053
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Am J Respir Crit Care Med. 2005 Mar 15;171(6):606-15
references.pmid: 15591471
references.citation: J Immunol. 2007 Dec 1;179(11):7791-9
references.pmid: 18025225
references.citation: J Immunol. 1986 Jun 1;136(11):4220-5
references.pmid: 3009619
references.citation: Biophys J. 2007 Jul 15;93(2):674-83
references.pmid: 17483162
references.citation: J Lipid Res. 2007 Dec;48(12):2762-8
references.pmid: 17848583
references.citation: Atherosclerosis. 2008 Jan;196(1):180-189
references.pmid: 17466310
references.citation: J Exp Med. 2009 Jan 16;206(1):61-8
references.pmid: 19124657
references.citation: J Lipid Res. 1999 Aug;40(8):1417-25
references.pmid: 10428977
references.citation: J Clin Invest. 2002 Jan;109(1):41-50
references.pmid: 11781349
references.citation: J Immunol. 2008 Mar 15;180(6):4273-82
references.pmid: 18322240
references.citation: J Immunol. 2007 Oct 1;179(7):4367-75
references.pmid: 17878331
references.citation: Circulation. 2008 Oct 28;118(18):1837-47
references.pmid: 18852364
references.citation: J Exp Med. 1999 Sep 20;190(6):875-80
references.pmid: 10499925
references.citation: Med Sci Monit. 2008 Aug;14(8):CS71-5
references.pmid: 18668002
references.citation: Shock. 2010 Feb;33(2):162-9
references.pmid: 19487981
references.citation: J Atheroscler Thromb. 2009 Jun;16(3):194-200
references.pmid: 19556716