Akhavanpoor Mohammadreza, Akhavanpoor Hamidreza, Gleissner Christian A, Wangler Susanne, Doesch Andreas O, Katus Hugo A, Erbel Christian
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Curr Drug Targets. 2017;18(7):863-873. doi: 10.2174/1389450117666161229142155.
A complex network of different cytokines and chemokines modulates atherosclerosis, a chronic inflammatory disease. Interleukin-17A (IL-17A) is expressed by different leukocyte subsets such as CD4+IL-17+ T cells (Th17), γδ T cells, natural killer cells, natural killer T cells, and neutrophils. IL-17A plays an important role in host defense and is involved in the pathology of different autoimmune and inflammatory diseases. Recent studies demonstrate an association of IL-17A with atherosclerosis. IL-17A seems to have primarily pro-inflammatory effects in atherogenesis, although there are partially controversial results in the literature. In the murine system, several studies indicate a pro-atherogenic role of IL-17A mediated by increased migration of leukocytes (especially macrophages) into atherosclerotic lesions, increased expression of pro-inflammatory cytokines and chemokines as well as plaque destabilizing matrix-metalloproteinases using Apoe-/- and LDLr-/- mice. In contrast, three studies show atheroprotective effects of IL-17A mediated by downregulation of aortic VCAM-1 expression on endothelial cells and increased collagen production by vascular smooth muscle cells (VSMCs) in LDLr-/- mice. In humans, expression of IL-17A was associated with increased inflammation and plaque vulnerability in human atherosclerotic lesions. Moreover, IL-17A induced a pro-inflammatory, pro-thrombotic, plaque-destabilizing, and cell-attracting response of the inflammatory milieu of human plaque tissue samples. Notably, a recently published study challenged these findings by showing a worse outcome of patients with acute myocardial infarction with low serum levels of IL-17A. In the following review, we will focus on the recent progress of functional studies of IL-17A in atherosclerosis and will try to collect explanations for the controversial data.
由不同细胞因子和趋化因子构成的复杂网络调节着动脉粥样硬化这一慢性炎症性疾病。白细胞介素-17A（IL-17A）由不同的白细胞亚群表达，如CD4+IL-17+ T细胞（Th17）、γδ T细胞、自然杀伤细胞、自然杀伤T细胞和中性粒细胞。IL-17A在宿主防御中发挥重要作用，并参与不同自身免疫性疾病和炎症性疾病的病理过程。最近的研究表明IL-17A与动脉粥样硬化有关。尽管文献中有部分有争议的结果，但IL-17A在动脉粥样硬化形成过程中似乎主要具有促炎作用。在小鼠模型系统中，多项研究表明，使用载脂蛋白E基因敲除（Apoe-/-）和低密度脂蛋白受体基因敲除（LDLr-/-）小鼠，IL-17A通过增加白细胞（尤其是巨噬细胞）向动脉粥样硬化病变部位的迁移、促炎细胞因子和趋化因子表达的增加以及斑块不稳定基质金属蛋白酶的表达，发挥促动脉粥样硬化作用。相比之下，有三项研究表明，在LDLr-/-小鼠中，IL-17A通过下调内皮细胞上主动脉血管细胞黏附分子-1（VCAM-1）的表达以及增加血管平滑肌细胞（VSMC）胶原蛋白的产生，发挥抗动脉粥样硬化作用。在人类中，IL-17A的表达与人类动脉粥样硬化病变中炎症增加和斑块易损性相关。此外，IL-17A诱导人类斑块组织样本炎症环境产生促炎、促血栓形成、斑块不稳定和细胞吸引反应。值得注意的是，最近发表的一项研究对这些发现提出了质疑，该研究表明血清IL-17A水平低的急性心肌梗死患者预后更差。在接下来的综述中，我们将重点关注IL-17A在动脉粥样硬化功能研究方面的最新进展，并试图收集对有争议数据的解释。
