Inhibition of IL-17A Attenuates Atherosclerotic Lesion Development in ApoE-Deficient Mice
Inhibition of IL-17A Attenuates Atherosclerotic Lesion Development in ApoE-Deficient Mice
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DOI：
10.4049/jimmunol.0901126
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发表时间：
2009-12-15
影响因子：
4.4
通讯作者：
Dengler, Thomas J.
中科院分区：
文献类型：
--
作者：
Erbel, Christian;Chen, Lili;Dengler, Thomas J.
（自动）免疫反应在动脉粥样硬化中的重要性越来越充分理解。表达IL-17A的T细胞可调节免疫细胞运输，启动（自动）免疫疾病的炎症和细胞因子产生。在人颈动脉斑块中，我们先前显示了产生IL-17A的T细胞和IL-23的存在。但是，尚未研究IL-17A对动脉粥样硬化的影响。在病变区域，牙菌体组成，细胞浸润，细胞因子表达和细胞凋亡后，检查了喂养标准周围饮食的8 wk GOLE载脂蛋白电子缺陷小鼠的主动脉根切片。治疗组（n = 15）接受了抗IL-17A AB，对照（n = 10）接受了无关的ABS。 IL-17A的抑制显着降低了动脉粥样硬化病变区域（P <0.001），最大狭窄（P <0.001）和病变的脆弱性。 IL-17A MAB处理的小鼠显示细胞浸润降低，内皮细胞和免疫细胞上激活标记的下调（例如VCAM-1）以及细胞因子/趋化因子分泌降低（例如，IL6，TNF Alpha，CCL5）。为了研究可能的机制，除了TNF-Alpha，IFN-GAMMA或LPS外，还通过IL-17A刺激了不同的动脉粥样硬化细胞类型（例如巨噬细胞，树突状细胞，HUVEC，血管平滑肌细胞），以诱导细胞激活或肥胖。体外。 IL-17A刺激在几种动脉粥样硬化细胞类型和鼠细胞中凋亡细胞死亡中诱导促炎性变化。 IL-17A的功能阻碍可减少动脉粥样硬化病变的发育，并减少载脂蛋白E缺陷小鼠的斑块脆弱性，细胞浸润和组织激活。目前的数据支持IL-17a通过对动脉粥样硬化细胞的广泛促炎和促凋亡作用的广泛促炎和促凋亡作用的致病作用。 《免疫学杂志》，2009，183：8167-8175。
The importance of an (auto)immune response in atherogenesis is becoming increasingly well understood. IL-17A-expressing T cells modulate immune cell trafficking, initiating inflammation and cytokine production in (auto)immune diseases. In human carotid artery plaques, we previously showed the presence of IL-17A-producing T cells and IL-23; however, IL-17A effects on atherogenesis have not been studied. Aortic root sections from 8-wk-old apolipoprotein E-deficient mice fed a standard chow diet were examined after 12 wk for lesion area, plaque composition, cellular infiltration, cytokine expression, and apoptosis. The treatment group (n = 15) received anti-IL-17A Ab and the controls (n = 10) received irrelevant Abs. Inhibition of IL-17A markedly reduced atherosclerotic lesion area (p < 0.001), maximal stenosis (p < 0.001), and vulnerability of the lesion. IL-17A mAb-treated mice showed reduced cellular infiltration, down-regulation of activation markers on endothelium and immune cells (e.g., VCAM-1), and reduced cytokine/chemokine secretion (e.g., IL6, TNF alpha, CCL5). To investigate possible mechanisms, different atherogenic cell types (e.g., macrophages, dendritic cells, HUVECs, vascular smooth muscle cells) were stimulated with IL-17A in addition to TNF-alpha, IFN-gamma, or LPS to induce cellular activation or apoptosis in vitro. Stimulation with IL-17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. Functional blockade of IL-17A reduces atherosclerotic lesion development and decreases plaque vulnerability, cellular infiltration, and tissue activation in apolipoprotein E-deficient mice. The present data support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread proinflammatory and proapoptotic effects on atherogenic cells. The Journal of Immunology, 2009, 183: 8167-8175.