Resident Intimal Dendritic Cells Accumulate Lipid and Contribute to the Initiation of Atherosclerosis
Resident Intimal Dendritic Cells Accumulate Lipid and Contribute to the Initiation of Atherosclerosis
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DOI：
10.1161/circresaha.109.210781
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发表时间：
2010-02-05
影响因子：
20.1
通讯作者：
Cybulsky, Myron I.
中科院分区：
文献类型：
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作者：
Paulson, Kim E.;Zhu, Su-Ning;Cybulsky, Myron I.
理由：动脉粥样硬化是一种白细胞和氧化脂质在动脉内膜中积聚的炎症性疾病。此前，我们发现树突状细胞（DC）优先聚集在正常小鼠主动脉内膜中易发生动脉粥样硬化的区域。这些细胞在动脉粥样硬化形成中的功能尚不清楚。目的：我们的目标是确定常驻内膜 DC 在动脉粥样硬化起始中的作用。方法和结果：对喂食富含胆固醇的饮食 5 或 10 天的低密度脂蛋白受体缺陷 (Ldlr(-/-)) 小鼠的新生动脉粥样硬化病变进行 Enface 免疫染色，结果表明泡沫 细胞表达 DC 标记物 CD11c、33D1 和主要组织相容性复合体 II 类。透射电子显微镜显示大部分内膜脂质位于细胞内。使用在 CD11c(+) 细胞中表达猿白喉毒素受体的转基因小鼠，通过条件性耗竭证实了常驻内膜 DC 在病变形成中的作用。单次注射白喉毒素可使内膜 CD11c(+) DC 在 24 小时内减少 98% 以上，1 周和 3 周分别恢复 25% 和 75%。当在 Ldlr(-/-) 背景上繁殖时，在病变形成的 5 天期间用白喉毒素去除内膜 DC，相对于未去除对照的内膜脂质面积减少了 55%。透射电子显微镜显示，DC耗尽的小鼠中泡沫细胞很少，内皮下细胞外脂质大量积累。结论：诱导小鼠高胆固醇血症会触发内膜DC对脂质的快速摄取，从而引发新生泡沫细胞病变的形成。 （Circ Res. 2010；106：383-390。）
Rationale: Atherosclerosis is an inflammatory disease in which leukocytes and oxidatively modified lipids accumulate in the arterial intima. Previously, we showed that dendritic cells (DCs) accumulate preferentially in regions predisposed to atherosclerosis in the normal murine aortic intima. The function of these cells in atherogenesis is unknown.Objective: Our goal was to determine the role of resident intimal DCs in the initiation of atherosclerosis.Methods and Results: En face immunostaining of nascent atherosclerotic lesions in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice fed a cholesterol-rich diet for 5 or 10 days demonstrated that foam cells expressed DC markers CD11c, 33D1, and major histocompatibility complex class II. Transmission electron microscopy revealed that the majority of intimal lipid was intracellular. The role of resident intimal DCs in lesion formation was verified by their conditional depletion using transgenic mice expressing the simian diphtheria toxin receptor in CD11c(+) cells. A single injection of diphtheria toxin depleted intimal CD11c(+) DCs by >98% within 24 hours, with 25% and 75% recovery at 1 and 3 weeks, respectively. When bred onto the Ldlr(-/-) background, intimal DC depletion with diphtheria toxin during 5 days of lesion formation reduced the intimal lipid area by 55% relative to undepleted controls. Transmission electron microscopy revealed few foam cells in DC-depleted mice and abundant accumulation of subendothelial extracellular lipid.Conclusions: Induction of hypercholesterolemia in mice triggers rapid ingestion of lipid by resident intimal DCs, which initiate nascent foam cell lesion formation. (Circ Res. 2010; 106: 383-390.)