J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.P700022-JLR200 on September 11, 2007

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Journal of Lipid Research, Vol. 48, 2762-2768, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis

Mary Jane Thomassen1,*, Barbara P. Barna*, Achut G. Malur{dagger}, Tracey L. Bonfield§, Carol F. Farver§,**, Anagha Malur*, Heidi Dalrymple*, Mani S. Kavuru* and Maria Febbraio{dagger}{dagger}

* Program in Lung Cell Biology and Translational Research, Division of Pulmonary and Critical Care Medicine, East Carolina University, Greenville, NC
{dagger} Department of Microbiology and Immunology, East Carolina University, Greenville, NC
§ Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH
** Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH
{dagger}{dagger} Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH

Published, JLR Papers in Press, September 11, 2007.

1 To whom correspondence should be addressed. e-mail: thomassenm{at}ecu.edu


ABSTRACT

Patients with pulmonary alveolar proteinosis (PAP) display impaired surfactant clearance, foamy, lipid-filled alveolar macrophages, and increased cholesterol metabolites within the lung. Neutralizing autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) are also present, resulting in virtual GM-CSF deficiency. We investigated ABCG1 and ABCA1 expression in alveolar macrophages of PAP patients and GM-CSF knockout (KO) mice, which exhibit PAP-like pulmonary pathology and increased pulmonary cholesterol. Alveolar macrophages from both sources displayed a striking similarity in transporter gene dysregulation, consisting of deficient ABCG1 accompanied by highly increased ABCA1. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a known regulator of both transporters, was deficient, as reported previously. In contrast, the liver X receptor {alpha}, which also upregulates both transporters, was highly increased. GM-CSF treatment increased ABCG1 expression in macrophages in vitro and in PAP patients in vivo. Overexpression of PPAR{gamma} by lentivirus-PPAR{gamma} transduction of primary alveolar macrophages, or activation by rosiglitazone, also increased ABCG1 expression. These results suggest that ABCG1 deficiency in PAP and GM-CSF KO alveolar macrophages is attributable to the absence of a GM-CSF-mediated PPAR{gamma} pathway. These findings document the existence of ABCG1 deficiency in human lung disease and highlight a critical role for ABCG1 in surfactant homeostasis.

Supplementary key words liver X receptor {alpha} • peroxisome proliferator-activated receptor {gamma} • ATP binding cassette transporter A1 • ATP binding cassette transporter G1 • foam cells • granulocyte-macrophage colony-stimulating factor


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