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

J Immunol. 2015 Nov 15;195(10):4685-98. doi: 10.4049/jimmunol.1500806. Epub 2015 Oct 14.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / immunology
  • Apolipoprotein A-I / metabolism*
  • Apolipoproteins E / metabolism
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology
  • Bone Marrow Transplantation
  • Cell Movement / immunology
  • Cholesterol / metabolism*
  • Dendritic Cells / immunology
  • Gas Chromatography-Mass Spectrometry
  • Linoleic Acids / metabolism
  • Lipoproteins, HDL / immunology
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / pathology
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR gamma / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / immunology

Substances

  • Apolipoprotein A-I
  • Apolipoproteins E
  • Autoantibodies
  • Linoleic Acids
  • Lipoproteins, HDL
  • PPAR gamma
  • 13-hydroxy-9,11-octadecadienoic acid
  • Cholesterol