Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.
Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.
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DOI：
10.1161/circulationaha.109.924886
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发表时间：
2010-04-20
期刊：
影响因子：
37.8
通讯作者：
Galkina E
中科院分区：
文献类型：
--
作者：
Smith E;Prasad KM;Butcher M;Dobrian A;Kolls JK;Ley K;Galkina E
T细胞在伴随动脉粥样硬化的免疫反应中起着重要作用。到目前为止，IL-17A在动脉粥样硬化形成中的作用尚不清楚。在这里，我们测试了易患动脉粥样硬化的条件诱导产生IL-17A的T细胞分化，进而促进动脉粥样硬化的假设。载脂蛋白E缺陷(apoE-−/−)小鼠血浆和组织中IL-17A水平升高。与年龄匹配的C57BL/6小鼠相比，老年−/−小鼠动脉、脾和固有层中IL-17A表达的T细胞显著增加。老年−/−小鼠IL-17A+T细胞分布于动脉和外膜。喂养15周的21周龄APOE−/−小鼠的主动脉中也检测到IL-17A+T细胞水平升高。IL-17A+T细胞以CD_4~+T细胞和γδ~+T细胞为主。用腺病毒产生的IL-17RA阻断APOE−/−小鼠中的IL-17A可以减少喂养15周西方饮食的APOE−/−小鼠的斑块负荷。此外，治疗还降低了循环中的IL-6和G-CSF水平，并限制了CXCL1的表达和主动脉内巨噬细胞的含量。相反，IL-17A处理从apoE−/−小鼠分离的整个主动脉，使用体外黏附试验，促进单核细胞黏附和cxcl1的表达。-这些结果表明，易发生动脉粥样硬化的情况会诱导产生IL-17A的T细胞分化。IL-17A通过促进单核/巨噬细胞向主动脉壁募集，在动脉粥样硬化形成过程中发挥促动脉粥样硬化炎症作用。
T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for IL-17A in atherogenesis is not well-defined. Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells, which in turn promote atherosclerosis. IL-17A was found elevated in the plasma and tissues of apolipoprotein E-deficient (Apoe−/−) mice. IL-17A-expressing T cells were significantly increased in the aortas, spleen and lamina propria of aged Apoe−/− mice compared to age-matched C57BL/6 mice. IL-17A+ T cells resided in both, adventitia and aortas of aged Apoe−/− mice on chow diet. Elevated levels of IL-17A+ T cells were also detected in the aortas of 21 week old Apoe−/− mice fed western diet for 15 weeks. IL-17A+ T cells were characterized as predominantly CD4+ Th17 and γδ+ T cells. Blockade of IL-17A in Apoe−/− mice using adenovirus-produced IL-17RA reduced plaque burden in Apoe−/− mice fed western diet for 15 weeks. Also, the treatment diminished circulating IL-6 and G-CSF levels, and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe−/− mice, using an ex vivo adhesion assay, promoted monocyte adhesion and CXCL1 expression. - These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells. IL-17A plays a pro-atherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.