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Am J Respir Crit Care Med. 2010 Aug 1;182(3):404-12. doi: 10.1164/rccm.200910-1580OC. Epub 2010 Apr 15.

ATP-binding cassette transporter G1 deficiency dysregulates host defense in the lung.

Author information

1
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

PMID:
20395559
PMCID:
PMC2921600
DOI:
10.1164/rccm.200910-1580OC
[Indexed for MEDLINE]
Free PMC Article
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