title: ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis.
abstract: Many metabolic diseases, including atherosclerosis, type 2 diabetes, pulmonary alveolar proteinosis, and obesity, have a chronic inflammatory component involving both innate and adaptive immunity. Mice lacking the ATP-binding cassette transporter G1 (ABCG1) develop chronic inflammation in the lungs, which is associated with the lipid accumulation (cholesterol, cholesterol ester, and phospholipid) and cholesterol crystal deposition that are characteristic of atherosclerotic lesions and pulmonary alveolar proteinosis. In this article, we demonstrate that specific lipids, likely oxidized phospholipids and/or sterols, elicit a lung-specific immune response in Abcg1(-/-) mice. Loss of ABCG1 results in increased levels of specific oxysterols, phosphatidylcholines, and oxidized phospholipids, including 1-palmitoyl-2-(5'-oxovaleroyl)-sn-glycero-3-phosphocholine, in the lungs. Further, we identify a niche-specific increase in natural Ab (NAb)-secreting B-1 B cells in response to this lipid accumulation that is paralleled by increased titers of IgM, IgA, and IgG against oxidation-specific epitopes, such as those on oxidized low-density lipoprotein and malondialdehyde-modified low-density lipoprotein. Finally, we identify a cytokine/chemokine signature that is reflective of increased B cell activation, Ab secretion, and homing. Collectively, these data demonstrate that the accumulation of lipids in Abcg1(-/-) mice induces the specific expansion and localization of B-1 B cells, which secrete NAbs that may help to protect against the development of atherosclerosis. Indeed, despite chronic lipid accumulation and inflammation, hyperlipidemic mice lacking ABCG1 develop smaller atherosclerotic lesions compared with controls. These data also suggest that Abcg1(-/-) mice may represent a new model in which to study the protective functions of B-1 B cells/NAbs and suggest novel targets for pharmacologic intervention and treatment of disease.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO 63104;
authors.forename: Angel
authors.initials: A
authors.lastname: Baldan
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093;
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095;
authors.forename: Christina
authors.initials: C
authors.lastname: Choung
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093;
authors.forename: Xuchu
authors.initials: X
authors.lastname: Que
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO 63104;
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Marquart
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior de Investigaciones Cientificas - Universidad Autonoma de Madrid, Madrid 28006; Unidad Asociada de Biomedicina IIBM-Universidad de Las Palmas de Gran Canaria, Las Palmas 35016, Spain; and.
authors.forename: Irene
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Karolinska Institutet, Stockholm 11 171, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Bjorkhem
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO 63104;
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093;
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095; ETarling@mednet.ucla.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology*; D030161:Avian Proteins / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D001402:B-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D030161:Avian Proteins; D016207:Cytokines; C071280:EMF-1 protein, Gallus gallus; D008074:Lipoproteins; D010743:Phospholipids