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Immunity. 2016 Dec 20;45(6):1311-1326. doi: 10.1016/j.immuni.2016.11.008.

Cholesterol Accumulation in CD11c+ Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease.

Author information

1
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
2
Departments of Medicine, Molecular & Cellular Biology and Biochemistry, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
3
Department of Medicine, University of California, San Diego, CA 92037, USA.
4
Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Cientificas y Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS), Universidad de las Palmas de Gran Canaria, Las Palmas, Spain.
5
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
6
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA. Electronic address: ptontonoz@mednet.ucla.edu.

Abstract

Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and β in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRβ-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE/LXR-β-deficient mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease.

KEYWORDS:

LXR; autoantibodies; autoimmune disease; reverse cholesterol transport

PMID:
28002731
PMCID:
PMC5181791
DOI:
10.1016/j.immuni.2016.11.008
[Indexed for MEDLINE]
Free PMC Article

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