title: Cholesterol Accumulation in CD11c+Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Departments of Medicine, Molecular & Cellular Biology and Biochemistry, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jon V
authors.initials: JV
authors.lastname: Salazar
authors.affiliation: Department of Medicine, University of California, San Diego, CA 92037, USA.
authors.forename: Cody
authors.initials: C
authors.lastname: Diehl
authors.affiliation: Department of Medicine, University of California, San Diego, CA 92037, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: 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.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Diaz
authors.affiliation: 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.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.affiliation: Departments of Medicine, Molecular & Cellular Biology and Biochemistry, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D039521:CD11c Antigen / Q000276:immunology; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006937:Hypercholesterolemia / Q000276:immunology / Q000378:metabolism*; D000071518:Liver X Receptors / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059467:Transcriptome
chemical_list: D039521:CD11c Antigen; D000071518:Liver X Receptors; D002784:Cholesterol
keywords: LXR; autoantibodies; autoimmune disease; reverse cholesterol transport