Blockade of Interleukin-17A Results in Reduced Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

Background— T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (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. Methods and Results— IL-17A was found to be 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 with age-matched C57BL/6 mice. IL-17A⁺ T cells resided in both adventitia and aortas of aged Apoe^−/− mice fed a chow diet. Elevated levels of IL-17A⁺ T cells were also detected in the aortas of 21-week-old Apoe^−/− mice fed a Western diet for 15 weeks. IL-17A⁺ T cells were characterized as predominantly CD4⁺ T helper 17 (Th17) cells and γδ⁺ T cells. Blockade of IL-17A in Apoe^−/− mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe^−/− mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe^−/− mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay. Conclusions— These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A–producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.