Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice.

Autor:	Black LL; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;, Srivastava R; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;, Schoeb TR; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; and., Moore RD; Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294., Barnes S; Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294., Kabarowski JH; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; janusz@uab.edu.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Nov 15; Vol. 195 (10), pp. 4685-98. Date of Electronic Publication: 2015 Oct 14.
DOI:	10.4049/jimmunol.1500806
Abstrakt:	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. (Copyright © 2015 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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