T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.
T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.
复制标题
T细胞胆固醇流出可抑制中年小鼠的细胞凋亡和衰老，并加剧动脉粥样硬化。
DOI：
10.1038/s41467-022-31135-4
复制
发表时间：
2022-07-01
影响因子：
16.6
通讯作者：
Westerterp, Marit
中科院分区：
文献类型：
--
作者：
Bazioti, Venetia;La Rose, Anouk M.;Maassen, Sjors;Bianchi, Frans;de Boer, Rinse;Halmos, Benedek;Dabral, Deepti;Guilbaud, Emma;Flohr-Svendsen, Arthur;Groenen, Anouk G.;Marmolejo-Garza, Alejandro;Koster, Mirjam H.;Kloosterhuis, Niels J.;Havinga, Rick;Pranger, Alle T.;Langelaar-Makkinje, Miriam;de Bruin, Alain;van de Sluis, Bart;Kohan, Alison B.;Yvan-Charvet, Laurent;van den Bogaart, Geert;Westerterp, Marit
动脉粥样硬化是一种由高胆固醇血症驱动的慢性炎症性疾病。在衰老过程中，T细胞会积累胆固醇，这可能影响炎症。然而，由ATP结合盒A1和G1（ABCA1/ABCG1）介导的胆固醇流出途径对T细胞依赖性年龄相关炎症和动脉粥样硬化的影响仍知之甚少。在这项研究中，我们在低密度脂蛋白受体缺陷（Ldlr−/−）背景下培育了T细胞特异性Abca1/Abcg1缺陷小鼠。T细胞Abca1/Abcg1缺陷会减少血液、淋巴结和脾脏中的T细胞，并增加T细胞的活化和凋亡。T细胞Abca1/Abcg1缺陷在中年（12 - 13个月）Ldlr−/−小鼠中诱导出一种过早的T细胞衰老表型，这表现为衰老标志物的上调。尽管存在T细胞衰老和T细胞活化增强的情况，但T细胞Abca1/Abcg1缺陷会减少中年Ldlr−/−小鼠的动脉粥样硬化和主动脉炎症，同时动脉粥样硬化斑块中的T细胞也会减少。我们将这些效应归因于T细胞活化后的T细胞凋亡，这损害了T细胞的功能。总之，我们表明T细胞胆固醇流出途径抑制T细胞凋亡和衰老，并在中年Ldlr−/−小鼠中诱导动脉粥样硬化。
胆固醇流出是由T细胞中的特定转运蛋白介导的。在此，作者表明当ABCA1/ABCG1胆固醇转运蛋白缺失时，中年Ldlr−/−小鼠外周T细胞数量减少，但活化增加，同时伴有T细胞衰老和凋亡的过早衰老表型。
Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr−/−) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12–13 months) Ldlr−/− mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr−/− mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr−/− mice. Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr−/− mice.
登录
查看更多内容
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
影响因子：
82.9
作者：
Fernandez, Dawn M.;Rahman, Adeeb H.;Giannarelli, Chiara
通讯作者：
Giannarelli, Chiara
DOI：
10.1038/s41577-019-0180-1
发表时间：
2019-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Goronzy JJ;Weyand CM
通讯作者：
Weyand CM
影响因子：
82.9
作者：
Ait-Oufella, H;Salomon, BL;Mallat, Z
通讯作者：
Mallat, Z
影响因子：
15.9
作者：
Cheng, Hsin-Yuan;Gaddis, Dalia E.;Hedrick, Catherine C.
通讯作者：
Hedrick, Catherine C.