Article

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: 14.95). 04/2010; 121(15):1746-55. DOI: 10.1161/CIRCULATIONAHA.109.924886
Source: PubMed

ABSTRACT 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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    • "IL-17A is a proinflammatory cytokine [12], highly produced in patients with chronic inflammatory International Journal of Inflammation diseases, such as RA, MS, and IBD [13] [14] [15]. IL-17A is also involved in atherosclerosis [16]; furthermore, in humans a positive correlation has also been found between circulating IL-17A levels and acute coronary syndrome [17] [18]. These findings have suggested that IL-17A might play a role in the cardiovascular risk associated with systemic immunological disorders. "
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    ABSTRACT: Interleukin-17A (IL-17A), the most widely studied member of the IL-17 cytokine family, is a cytokine which emerged to be critical for host defense as well as in the pathogenesis of autoimmune disorders. Moreover, IL-17A is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis and acute coronary syndrome and in the cardiovascular risk associated with systemic immunological disorders. Consistent with this, we have recently shown that IL-17A increases human and murine platelet response to ADP. In this study we expanded our previous observation and we describe for the first time an in vivo prothrombotic effect of the cytokine. Our results show that IL-17A is synergic with a low FeCl3 concentration in inducing carotid thrombus in rats and suggest that the effect is likely related to a downregulation of CD39 vascular expression and hydrolyzing activity. Our findings indicate that IL-17A might be an important molecule at the interface between hemostasis and inflammation. “This paper is dedicated to the memory of Professor Alfredo Colonna”
    04/2014; 2014:247503. DOI:10.1155/2014/247503
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    • "Based on their potent production of pro-inflammatory cytokines such as IFNg and IL-17 [9] [10], they are surmised to be pro-atherogenic. In fact, Smith et al. reported that approximately 50% or more IL-17 þ CD3 þ cells in the aorta and spleen are gd T cells [11]. However, the exact, direct role that gd T cells play in either driving or protecting against atherosclerosis is unknown. "
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    • "Nevertheless, the majority of pre-clinical studies do not consider co-morbidities such as hypercholesterolemia, which are frequently shown in stroke patients. Hypercholesterolemia does not only promote atherosclerotic plaque development but also induces local inflammation within the vessel wall of peripheral arteries, which is associated with broad systemic immune changes, affecting almost all immune cell subtypes of the innate and adaptive immune system (Drechsler et al., 2010; Smith et al., 2010; Wu et al., 2009). A few pre-clinical studies emphasize the role of the immune system in the combined setting of hyperlipidemia and stroke, but are hampered due to focusing on single molecules and immune cell subsets (Kim et al., 2008). "
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