Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis
复制标题
DOI：
10.1172/jci63891
复制
发表时间：
2013-03-01
影响因子：
15.9
通讯作者：
Hansson, Goran K.
中科院分区：
文献类型：
--
作者：
Klingenberg, Roland;Gerdes, Norbert;Hansson, Goran K.
动脉粥样硬化是一种由高脂血症引起的慢性炎症性疾病。一些研究支持FOXP 3阳性调节性T细胞（TCFs）作为动脉粥样硬化的抑制剂;然而，这种保护的机制仍然难以捉摸。为了确定FOXP 3-表达Tcl 3在动脉粥样硬化中的作用，我们使用DEREG小鼠，其在Treg-特异性Foxp 3启动子的控制下表达白喉毒素（DT）受体，允许特异性消融FOXP 3（+）Tcl 3。经致死性照射、易患动脉粥样硬化、低密度脂蛋白受体缺陷（Ldlr（-/-））小鼠接受DEREG骨髓，并注射DT以消除FOXP 3（+）TfR。TdR的消耗导致动脉粥样硬化增加2.1倍，而没有伴随血管炎症的增加。这些小鼠还表现出血浆胆固醇增加1.7倍，致动脉粥样硬化脂蛋白谱和VLDL水平增加。VLDL和乳糜微粒残留物的清除受到阻碍，导致富含胆固醇的颗粒在循环中积聚。功能和蛋白质分析补充基因表达阵列确定减少分拣蛋白-1在肝脏中的蛋白质表达和增加脂蛋白脂肪酶，肝脂肪酶和磷脂转移蛋白的血浆酶活性作为介质的脂质表型改变。这些结果表明，FOXP 3（+）T β通过调节脂蛋白代谢抑制动脉粥样硬化。
Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3(+) Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.