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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Available from: Anca D Dobrian, Feb 20, 2015
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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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    ABSTRACT: Gammadelta (γδ) T cells are a subset of pro-inflammatory innate-like T lymphocytes that serve as a bridge between innate and adaptive immunity. γδ T cells are highly enriched in cholesterol compared to αβ T cells. In this study, we aimed to identify the role of γδ T cells in atherosclerosis, a cholesterol and inflammation-driven disease. We found that the percentages of γδ T cells are increased in ApoE(-/-) mice fed a Western diet. We generated TCRδ(-/-)ApoE(-/-) mice and fed them either rodent chow or a Western diet for ten weeks for the assessment of atherosclerosis. The atherosclerotic lesion size in diet-fed TCRδ(-/-)ApoE(-/-) mice was similar to that of diet-fed ApoE(-/-) mice. There were no differences in cytokine production or numbers of αβ T cells in aorta of TCRδ(-/-)ApoE(-/-) mice. Plasma lipoprotein profiles were unchanged by the absence of γδ T cells. Our data suggest that γδ T cells do not contribute to early atherosclerotic plaque development.
    Atherosclerosis 03/2014; 234(2):265-269. DOI:10.1016/j.atherosclerosis.2014.03.007 · 3.97 Impact Factor
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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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    ABSTRACT: Inflammation contributes to ischemic brain injury. However, translation of experimental findings from animal models into clinical trials is still ineffective, since the majority of human stroke studies mainly focuses on acute neuroprotection, thereby neglecting inflammatory mechanisms and inflammation-associated co-morbidity factors such as hypercholesterolemia. Therefore, both wildtype and ApoE(-/-) mice that exhibit increased serum plasma cholesterol levels fed with normal or high cholesterol diet were exposed to transient middle cerebral artery occlusion. Analysis of peripheral immune responses revealed an ischemia-induced acute leukocytosis in the blood, which was accompanied by enhanced myeloid cell and specifically granulocyte cell counts in the spleen and blood of ApoE(-/-) mice fed with Western diet. These cellular immune changes were further associated with increased levels of pro-inflammatory cytokines like IL-6 and TNF-α. Moreover, endogenous stroke-induced endothelial activation as well as CXCL-1 and CXCL-2 expression were increased, thus resulting in accelerated leukocyte, particularly granulocyte accumulation, and enhanced ischemic tissue damage. The latter was revealed by larger infarct volumes and increased local DNA fragmentation in ischemic brains of ApoE(-/-) mice on Western diet. These effects were not observed in wildtype mice on normal or Western diet and in ApoE(-/-) mice on normal diet. Our data demonstrate that the combination of both ApoE knockout and a high cholesterol diet leads to increased ischemia-induced peripheral and cerebral immune responses, which go along with enhanced cerebral tissue injury. Thus, clinically predisposing conditions related to peripheral inflammation such as hypercholesterolemia should be included in up-coming preclinical stroke research.
    Neurobiology of Disease 10/2013; 62. DOI:10.1016/j.nbd.2013.10.022 · 5.20 Impact Factor
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