Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice
Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice
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DOI：
10.1096/fj.09-148155
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发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Boisvert, William A.
中科院分区：
文献类型：
--
作者：
Han, Xinbing;Kitamoto, Shiro;Boisvert, William A.
在动脉粥样硬化形成过程中，巨噬细胞泡沫细胞的形成受到胆固醇摄取和外流途径的调节。我们最近发现，白介素10(IL-10)通过促进巨噬细胞对胆固醇的摄取和外流来调节脂质代谢。然而，这些特性在体内的机制细节一直不清楚。因此，本研究的目的是确定IL-10在巨噬细胞中的表达是否会改变动脉粥样硬化的易感性，以及IL-10是否通过调节巨噬细胞的脂代谢来发挥其抗动脉粥样硬化的作用。我们利用了一种巨噬细胞特异性逆转录病毒载体，通过逆转录病毒转导的骨髓细胞(BMC)移植，允许在巨噬细胞中长期表达IL-10。来自转导的骨髓细胞的巨噬细胞表达的IL-10通过减少胆固醇酯在动脉粥样硬化部位的积聚来抑制LDLR-/-小鼠的动脉粥样硬化。对原代巨噬细胞的实验表明，巨噬细胞来源的IL-10既能刺激胆固醇的摄取(通过上调清道夫受体)，又能刺激胆固醇的流出(通过激活PPAR-Gamma-LXR-ABCA1/Abcg1途径)，从而减少动脉粥样硬化中的炎症和细胞凋亡。这些发现表明，BMC转导的巨噬细胞IL-10的产生可以作为一种强大的抗动脉粥样硬化药物，它们突出了一种使用简单但有效的干细胞转导系统的新的抗动脉粥样硬化治疗方法，该系统促进了IL-10在巨噬细胞中的长期表达。-HAN，X.，Kitamoto，S.，Wang，H.，Boisvert，W.A.巨噬细胞中IL-10的过表达抑制高脂血症小鼠的动脉粥样硬化。FASE B J.24,2869-2880(2010)。Www.fasebj.org
In atherogenesis, macrophage foam cell formation is modulated by pathways involving both the uptake and efflux of cholesterol. We recently showed that interleukin-10 (IL-10) modulates lipid metabolism by enhancing both uptake and efflux of cholesterol in macrophages. However, the mechanistic details of these properties in vivo have been unclear. Thus, the purpose of this study was to determine whether expression of IL-10 in macrophages would alter susceptibility to atherosclerosis and whether IL-10 exerts its antiatherosclerotic properties by modulating lipid metabolism in macrophages. We utilized a macrophage-specific retroviral vector that allows long-term in vivo expression of IL-10 in macrophages through transplantation of retrovirally transduced bone marrow cells (BMCs). IL-10 expressed by macrophages derived from transduced BMCs inhibited atherosclerosis in LDLR-/- mice by reducing cholesteryl ester accumulation in atherosclerotic sites. Experiments with primary macrophages indicated that macrophage source of IL-10 stimulated both the uptake (by up-regulating scavenger receptors) and efflux of cholesterol (by activating the PPAR gamma-LXR-ABCA1/ABCG1 pathway), thereby reducing inflammation and apoptosis in atherosclerosis. These findings indicate that BMC-transduced macrophage IL-10 production can act as a strong antiatherogenic agent, and they highlight a novel antiatherosclerotic therapy using a simple, yet effective, stem cell transduction system that facilitates long-term expression of IL-10 in macrophages.-Han, X., Kitamoto, S., Wang, H., Boisvert, W. A. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 24, 2869-2880 (2010). www.fasebj.org