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

Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA.
Circulation (Impact Factor: 14.43). 04/2010; 121(15):1746-55. DOI: 10.1161/CIRCULATIONAHA.109.924886
Source: PubMed


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.
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 gammadelta(+) 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.
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.

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Available from: Anca D Dobrian, Feb 20, 2015
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    • "Several studies indicated that Th1 cells had a proatherogenic role since blocking Th1 polarization by pentoxifylline significantly attenuated atherosclerotic lesion development in experimental atherosclerosis mice model [3]. In addition, it has been reported that Th17 cells were also deeply involved in the development of atherosclerotic lesions [4], [5]. The up-regulation of Th17 response was observed in both local atherosclerotic plaque and circulating lymphocytes which accelerated atherosclerotic lesion formation. "
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    ABSTRACT: Accumulating evidence indicates that both defects in Treg numbers and/or function as well as resistance of effector T cells to suppression may contribute to the development of human chronic inflammatory diseases. However, which mechanism involved in the progression of atherosclerosis remains unclear. In this study, we evaluated the production and function of CD4+ inflammatory and regulatory T cells in atherosclerosis-prone mice. We found that the hyperactivity and unresponsiveness to Treg-mediated suppression of inflammatory CD4+ T cells occurred in the progression of atherosclerosis, though Treg cells were present in very large numbers and fully functional. We further found that Gr-1+CD11b+ immature myeloid cells were significantly accumulated in atherosclerotic Apo E-/- mice, and they promoted resistance of inflammatory CD4+ T cells to Treg-mediated suppression in vitro and in vivo. we further confirmed that Gr-1+CD11b+ immature myeloid cells produced high level of interleukin 6 which was at least partially responsible for inducing unresponsiveness of inflammatory CD4+ T cells to suppression via activation of Jak/Stat signaling pathway. Taken together, these findings might provide new insights to explore potential targets for immune therapeutic intervention in atherosclerosis.
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    • "Macrophages were the first well-described inflammatory participant in T2D as well as atherosclerosis, whose recruitment directly contributed to the systemic inflammatory status and plaque formation [24]. More recently, however, it is revealed that an elevation of Th1 and Th17 subsets [25, 26] accompanied by a significant decrease of regulatory T cells (Tregs) [27] may directly trigger the activation and infiltration of macrophage and thus systemic or local inflammation in the development of atherosclerosis and CHD [28]. However, the exact roles and underlying mechanisms of the Th subsets in CHD were far from being elucidated. "
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