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J Immunol. 2014 Dec 1;193(11):5637-48. doi: 10.4049/jimmunol.1400606. Epub 2014 Oct 22.

ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis.

Author information

1
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;
2
Department of Medicine, University of California San Diego, La Jolla, CA 92093;
3
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095;
4
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO 63104;
5
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.
6
Karolinska Institutet, Stockholm 11 171, Sweden.
7
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095; ETarling@mednet.ucla.edu.

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.

PMID:
25339664
PMCID:
PMC4239162
DOI:
10.4049/jimmunol.1400606
[Indexed for MEDLINE]
Free PMC Article

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