Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice.
Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice.
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DOI：
10.4049/jimmunol.1500806
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发表时间：
2015-11-15
期刊：
影响因子：
--
通讯作者：
Kabarowski JH
中科院分区：
文献类型：
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作者：
Black LL;Srivastava R;Schoeb TR;Moore RD;Barnes S;Kabarowski JH
载脂蛋白A-I(ApoA-I)是高密度脂蛋白(高密度脂蛋白)的主要脂结合蛋白，通过抑制淋巴细胞胆固醇蓄积和清除组织氧化脂质来预防高胆固醇血症小鼠的自身免疫和抑制炎症反应。然而，在正常胆固醇血症条件下，载脂蛋白A-I是否介导免疫抑制或抗炎作用及其涉及的机制仍未解决。我们将易患系统性红斑狼疮的Sle123小鼠的骨髓移植到正常、载脂蛋白A-I基因敲除(ApoA-I−/−)和载脂蛋白A-I转基因(ApoA-Itg)小鼠。在ApoA-ITG小鼠中，ApoA-I的增加抑制了CD4+T和B细胞的激活，而不改变淋巴细胞胆固醇水平或减少主要的ApoA-I结合的氧化脂肪酸。出乎意料的是，自身免疫性ApoA-γ小鼠淋巴细胞中氧化脂肪酸过氧化物酶体增殖物激活受体γ(PPAR)配体13-羟基十八碳二烯酸(HODE)和9-HODE增加。载脂蛋白A-I可减少Th1细胞，而与CD4+FoxP3+调节性T细胞或CD11c+树突状细胞活化和迁移的变化无关。ApoA-ITG小鼠的卵泡辅助T细胞、生发中心B细胞和自身抗体水平也较低。转基因载脂蛋白A-I也改善了SLE介导的肾小球肾炎。然而，ApoA-I缺乏对自身免疫或肾小球肾炎没有相反的影响，可能是由于高密度脂蛋白上的ApoE代偿性增加所致。我们的结论是，尽管代偿机制阻止了正常胆固醇血症小鼠ApoA-I缺乏的促炎作用，但增加ApoA-I可以减弱系统性红斑狼疮患者的淋巴细胞激活和自身免疫，而不依赖于胆固醇的运输，这可能是通过氧化脂肪酸PPARγ配体实现的，并可以减轻肾小球肾炎的肾脏炎症。
Apolipoprotein A-I (ApoA-I), the major lipid-binding protein of high-density lipoprotein (HDL), 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 in normocholesterolemic conditions and the mechanisms involved remain unresolved. We transferred bone marrow from SLE-prone Sle123 mice into normal, ApoA-I knockout (ApoA-I−/−) and ApoA-I transgenic (ApoA-Itg) mice. Increased ApoA-I in ApoA-Itg 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 gamma (PPARγ) ligands 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE were increased in lymphocytes of autoimmune ApoA-Itg 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-Itg mice. Transgenic ApoA-I also improved SLE-mediated glomerulonephritis. However, ApoA-I deficiency did not have opposite effects on autoimmunity or glomerulonephritis, possibly due to compensatory increases of ApoE on HDL. We conclude that although compensatory mechanisms prevent pro-inflammatory 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 PPARγ ligands, and can reduce renal inflammation in glomerulonephritis.
影响因子：
3.7
作者：
Sontag TJ;Reardon CA
通讯作者：
Reardon CA