Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity.
Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity.
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DOI：
10.1016/j.cmet.2017.04.005
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发表时间：
2017-06-06
期刊：
影响因子：
29
通讯作者：
Tall AR
中科院分区：
文献类型：
--
作者：
Westerterp M;Gautier EL;Ganda A;Molusky MM;Wang W;Fotakis P;Wang N;Randolph GJ;D'Agati VD;Yvan-Charvet L;Tall AR
自身免疫性疾病如系统性红斑狼疮（SLE）与心血管疾病的增加和血浆高密度脂蛋白（HDL）水平的降低有关。HDL通过ATP结合盒转运蛋白A1和G1（ABCA 1/G1）介导胆固醇从免疫细胞流出。胆固醇流出途径受损在自身免疫中的意义尚不清楚。我们观察到Abca 1/g1缺陷小鼠出现淋巴结肿大和肾小球肾炎，提示SLE。这种狼疮样表型在树突状细胞（DC）中Abca 1/g1敲除的小鼠中重现，但在巨噬细胞或T细胞中没有。DC-Abca 1/g1缺陷增加LN和脾CD 11b + DC，其显示胆固醇积聚和炎性小体活化，增加GM-CSF受体的细胞表面水平，并增强炎性细胞因子分泌。因此，DC-Abca 1/g1缺陷增强T细胞活化，Th 1和Th 17细胞极化。NLRP 3炎性小体缺乏减少了扩大的LN和增强的Th 1细胞极化。这些发现确定了DC胆固醇流出途径在维持免疫耐受中的重要作用。自身免疫性疾病如系统性红斑狼疮（SLE）与血浆高密度脂蛋白（HDL）水平降低有关。HDL通过ATP结合盒转运蛋白A1和G1（ABCA 1/G1）介导胆固醇从免疫细胞流出。我们发现，DC Abca 1/g1缺陷小鼠的DC胆固醇积累促进炎性小体激活和自身免疫。
Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoproteins (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1 deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs) but not in macrophages or T-cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b+ DCs, which displayed cholesterol accumulation and inflammasome activation, increased cell surface levels of the GM-CSF receptor, and enhanced inflammatory cytokine secretion. Consequently, DC-Abca1/g1 deficiency enhanced T-cell activation, Th1 and Th17-cell polarization. NLRP3 inflammasome deficiency diminished the enlarged LNs and enhanced Th1-cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance. Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with reduced plasma high-density lipoproteins (HDL) levels. HDL mediates cholesterol efflux from immune cells via ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1). We show that DC cholesterol accumulation in mice with DC Abca1/g1 deficiency promotes inflammasome activation and autoimmunity.
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DOI：
10.4049/jimmunol.0902372
发表时间：
2010-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Armstrong AJ;Gebre AK;Parks JS;Hedrick CC
通讯作者：
Hedrick CC
DOI：
10.1084/jem.20150568
发表时间：
2016-02-08
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lin CC;Bradstreet TR;Schwarzkopf EA;Jarjour NN;Chou C;Archambault AS;Sim J;Zinselmeyer BH;Carrero JA;Wu GF;Taneja R;Artyomov MN;Russell JH;Edelson BT
通讯作者：
Edelson BT
影响因子：
13.3
作者：
Kahlenberg, J. Michelle;Yalavarthi, Srilakshmi;Zhao, Wenpu;Hodgin, Jeffrey B.;Reed, Tamra J.;Tsuji, Noriko M.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.
影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
32.4
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
通讯作者：
Tontonoz, Peter