IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.
IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.
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DOI：
10.1093/cvr/cvv110
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发表时间：
2015-06
影响因子：
10.8
通讯作者：
Wen-cai Zhang;T. Tang;Daan Nie;Shuang Wen;Chenping Jia;Zhengfeng Zhu;Ni Xia;Shaofang Nie;Su-feng Zhou;Jiao Jiao-Jiao;Wen-Yong Dong;Bing-Jie Lv;T. Xu;Bing Sun;Yuzhi Lu;Yuanyuan Li;Longxian Cheng;Yuhua Liao;Xiang Cheng
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文献类型：
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作者：
Wen-cai Zhang;T. Tang;Daan Nie;Shuang Wen;Chenping Jia;Zhengfeng Zhu;Ni Xia;Shaofang Nie;Su-feng Zhou;Jiao Jiao-Jiao;Wen-Yong Dong;Bing-Jie Lv;T. Xu;Bing Sun;Yuzhi Lu;Yuanyuan Li;Longxian Cheng;Yuhua Liao;Xiang Cheng
目的近年来发现白细胞介素9（IL-9）参与多种炎症性疾病的发病机制。在这里，我们测试了IL-9是否与动脉粥样硬化有关，并研究了其潜在机制。方法和结果IL-9 R在小鼠主动脉内皮细胞（MAECs）和主动脉组织中表达，载脂蛋白E缺陷（ApoE-/-）小鼠血浆和主动脉弓中IL-9水平升高。给予喂食西方饮食10周的ApoE-/-小鼠重组小鼠IL-9（rIL-9）或抗IL-9中和单克隆抗体（mAb）。用rIL-9处理的小鼠在主动脉和主动脉根部都产生了明显更大的斑块。免疫组织化学研究表明，增加血管内皮细胞粘附分子-1（VCAM-1）的表达和炎症细胞，包括T细胞和巨噬细胞的浸润，斑块。然而，用抗IL-9 mAb处理引起相反的效果。rIL-9的施用不影响脾T细胞或外周血单核细胞亚群。同时，IL-9主要通过STAT 3依赖性途径诱导MAEC表达VCAM-1，从而增加单核细胞-内皮细胞粘附。此外，用抗VCAM-1 mAb治疗部分消除了IL-9诱导的斑块面积增加。此外，急性冠脉综合征患者外周血CD 4 + IL-9 + T细胞和IL-9水平升高，且患者外周血培养上清IL-9水平与血浆可溶性VCAM-1（sVCAM-1）水平呈显著正相关。结论IL-9至少部分通过诱导VCAM-1表达，介导炎症细胞浸润动脉粥样硬化病变，从而发挥其促动脉粥样硬化作用。
AIMS Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.