ATP-binding Cassette Transporter G1 Deficiency Dysregulates Host Defense in the Lung

• Published in: American journal of respiratory and critical care medicine Vol. 182; no. 3; pp. 404 - 412
• Main Authors: DRAPER, David W, MADENSPACHER, Jennifer H, DIXON, Darlene, KING, Debra H, REMALEY, Alan T, FESSLER, Michael B
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.08.2010
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - physiology; Bacteria; Biological and medical sciences; Blood coagulation. Blood cells; Bronchoalveolar Lavage Fluid - cytology; Chemokines; Cholesterol; Coagulation factors; Cytokines; Cytokines - metabolism; Defense; Fundamental and applied biological sciences. Psychology; G. Pulmonary Infections; Gene Deletion; Genotype & phenotype; Gram-negative bacteria; Immunity, Innate; Infections; Intensive care medicine; Klebsiella pneumoniae; Laboratory animals; Lavage; Leukocyte Count; Leukocytes - metabolism; Lipopolysaccharides - administration & dosage; Lipoproteins - genetics; Lipoproteins - physiology; Lung - immunology; Lung - metabolism; Macrophages - metabolism; Macrophages - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Neutrophil Activation; Neutrophils; Neutrophils - metabolism; Proteins; Public health; Tumor necrosis factor-TNF; United States > US; Lung disease; Pneumonia; Intensive care; Respiratory disease; Deficiency; Lipids; Organism defense; ATP binding cassette G1; Immunity; Cholesterol; lung; innate immunity; ATP; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200910-1580oc

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. To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms. 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. 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. Abcg1(-/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.