Cholesterol Accumulation in CD11c(+) Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease.
Cholesterol Accumulation in CD11c(+) Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease.
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胆固醇在CD11c（+）免疫细胞中的积累是自身免疫性疾病的一个原因和靶向因素。
DOI：
10.1016/j.immuni.2016.11.008
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发表时间：
2016-12-20
期刊：
影响因子：
32.4
通讯作者：
Tontonoz, Peter
中科院分区：
文献类型：
--
作者：
Ito, Ayaka;Hong, Cynthia;Oka, Kazuhiro;Salazar, Jon V.;Diehl, Cody;Witztum, Joseph L.;Diaz, Mercedes;Castrillo, Antonio;Bensinger, Steven J.;Chan, Lawrence;Tontonoz, Peter
肝脏X受体（LXRs）是胆固醇代谢的调节剂，也调节免疫反应。小鼠中LXR α和β的失活导致自身免疫;然而，胆固醇代谢的调节如何促进自身免疫尚不清楚。在这里，我们发现，CD 11 c+细胞的胆固醇负荷触发了自身免疫的发展，而通过促进胆固醇流出来防止过量的脂质积累是治疗性的。LXRβ缺陷小鼠与高脂血症ApoE缺陷背景杂交或用高胆固醇饮食激发产生自身抗体。胆固醇在淋巴器官的积累促进T细胞的启动和刺激生产的B细胞生长因子Baff和四月。相反，ApoE−/−Lxrβ−/−小鼠中的B细胞扩增和自身抗体的产生被ApoA-I表达逆转。这些发现暗示胆固醇失衡是免疫功能障碍的一个因素，并表明刺激HDL依赖性胆固醇逆向转运可能对自身免疫性疾病有益。
Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and β in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRβ-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE−/−Lxrβ−/− mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease.
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DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Joseph, SB;Bradley, MN;Tontonoz, P
通讯作者：
Tontonoz, P
影响因子：
16
作者：
Ghisletti, Serena;Huang, Wendy;Glass, Christopher K.
通讯作者：
Glass, Christopher K.
影响因子：
27.4
作者：
Charles-Schoeman C;Lee YY;Grijalva V;Amjadi S;FitzGerald J;Ranganath VK;Taylor M;McMahon M;Paulus HE;Reddy ST
通讯作者：
Reddy ST
影响因子：
7.7
作者：
Ito A;Hong C;Rong X;Zhu X;Tarling EJ;Hedde PN;Gratton E;Parks J;Tontonoz P
通讯作者：
Tontonoz P