13-hydroxy-9-11-octadecadienoic-acid and Lupus-Nephritis

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.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins E; Autoantibodies; Autoimmunity; B-Lymphocytes; Bone Marrow Transplantation; Cell Movement; Cholesterol; Dendritic Cells; Gas Chromatography-Mass Spectrometry; Linoleic Acids; Lipoproteins, HDL; Lupus Nephritis; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; T-Lymphocytes, Regulatory; Th1 Cells