Stöger J Lauran, Boshuizen Marieke C S, Brufau Gemma, Gijbels Marion J J, Wolfs Ine M J, van der Velden Saskia, Pöttgens Chantal C H, Vergouwe Monique N, Wijnands Erwin, Beckers Linda, Goossens Pieter, Kerksiek Anja, Havinga Rick, Müller Werner, Lütjohann Dieter, Groen Albert K, de Winther Menno P J
Prof. M. P. J. de Winther, PhD, Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands, Tel.: +31 20 5666762, E-mail:
Thromb Haemost. 2016 Aug 30;116(3):565-77. doi: 10.1160/TH16-01-0043. Epub 2016 Jun 30.
Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.
炎症反应与胆固醇稳态在动脉粥样硬化形成过程中相互关联。白细胞介素（IL）-10是一种重要的抗炎细胞因子，已知其可抑制动脉粥样硬化的发展。然而，负责IL-10抗动脉粥样硬化作用的具体细胞类型仍有待确定，并且关于IL-10在胆固醇稳态中作用的知识也很匮乏。在此，我们研究了髓样细胞IL-10介导的抗动脉粥样硬化保护作用的功能参与情况。为此，将白细胞介素-10受体1（IL-10R1）野生型和髓样细胞IL-10R1缺陷型小鼠的骨髓移植到经致死剂量照射的雌性低密度脂蛋白受体基因敲除（LDLR-/-）小鼠体内。此后，给小鼠喂食高胆固醇饮食10周，之后研究动脉粥样硬化的发展和胆固醇代谢情况。在体外，髓样细胞IL-10R1缺陷导致促炎巨噬细胞表型。然而，在体内观察到病变大小和严重程度显著降低。这种表型与病变中髓样细胞积累减少和更多细胞凋亡有关。此外，在髓样细胞IL-10R1缺陷时，观察到血浆和肝脏胆固醇显著降低，这反映在斑块脂质含量上。这种高胆固醇血症的减轻与极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）水平降低有关，这可能是对肠道胆固醇吸收减少的一种反应。此外，IL-10R1缺陷型小鼠由于非胆汁胆固醇流出增加，粪便固醇损失显著更高。这一过程的诱导与酰基辅酶A胆固醇酰基转移酶2（ACAT2）介导的肝脏和血浆胆固醇酯化受损有关。总体而言，髓样细胞对IL-10介导的抗动脉粥样硬化保护作用没有贡献。此外，本研究证明了IL-10介导的炎症与动脉粥样硬化中胆固醇稳态之间的新联系。这些发现使我们重新考虑IL-10对动脉粥样硬化的有益影响。
