title: Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice.
abstract: Apolipoprotein (Apo)A-I, the major lipid-binding protein of high-density lipoprotein, can prevent autoimmunity and suppress inflammation in hypercholesterolemic mice by attenuating lymphocyte cholesterol accumulation and removing tissue-oxidized lipids. However, whether ApoA-I mediates immune-suppressive or anti-inflammatory effects under normocholesterolemic conditions and the mechanisms involved remain unresolved. We transferred bone marrow from systemic lupus erythematosus (SLE)-prone Sle123 mice into normal, ApoA-I-knockout (ApoA-I(-/-)) and ApoA-I-transgenic (ApoA-I(tg)) mice. Increased ApoA-I in ApoA-I(tg) mice suppressed CD4(+) T and B cell activation without changing lymphocyte cholesterol levels or reducing major ApoA-I-binding oxidized fatty acids. Unexpectedly, oxidized fatty acid peroxisome proliferator-activated receptor γ ligands 13- and 9-hydroxyoctadecadienoic acid were increased in lymphocytes of autoimmune ApoA-I(tg) mice. ApoA-I reduced Th1 cells independently of changes in CD4(+)Foxp3(+) regulatory T cells or CD11c(+) dendritic cell activation and migration. Follicular helper T cells, germinal center B cells, and autoantibodies were also lower in ApoA-I(tg) mice. Transgenic ApoA-I also improved SLE-mediated glomerulonephritis. However, ApoA-I deficiency did not have the opposite effects on autoimmunity or glomerulonephritis, possibly as the result of compensatory increases in ApoE on high-density lipoprotein. We conclude that, although compensatory mechanisms prevent the proinflammatory effects of ApoA-I deficiency in normocholesterolemic mice, increasing ApoA-I can attenuate lymphocyte activation and autoimmunity in SLE independently of cholesterol transport, possibly through oxidized fatty acid peroxisome proliferator-activated receptor γ ligands, and it can reduce renal inflammation in glomerulonephritis.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Leland L
authors.initials: LL
authors.lastname: Black
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Roshni
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; and.
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.affiliation: Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Ray D
authors.initials: RD
authors.lastname: Moore
authors.affiliation: Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; janusz@uab.edu.
authors.forename: Janusz H
authors.initials: JH
authors.lastname: Kabarowski
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001057:Apolipoproteins E / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000276:immunology; D002784:Cholesterol / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D008401:Gas Chromatography-Mass Spectrometry; D008041:Linoleic Acids / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D001323:Autoantibodies; D008041:Linoleic Acids; D008075:Lipoproteins, HDL; D047495:PPAR gamma; C024348:13-hydroxy-9,11-octadecadienoic acid; D002784:Cholesterol