Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
J Am Heart Assoc. 2012 Oct;1(5):e004408. doi: 10.1161/JAHA.112.004408. Epub 2012 Oct 25.
Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited.
We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas >90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression.
The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.
左心室（LV）重构导致慢性心力衰竭，是心肌梗死后发病率和死亡率的主要决定因素。目前，预防 LV 重构的治疗选择有限。
我们通过永久性结扎冠状动脉造成大面积心肌梗死，并确定白细胞介素（IL）-23/IL-17A 轴与影响 MI 后晚期 LV 重构的 γδT 细胞之间存在潜在联系。尽管手术后 24 小时的梗死面积与野生型小鼠相似，但 IL-23、IL-17A 或 γδT 细胞的缺乏可改善 7 天后的存活率，限制非梗死心肌的梗死扩张和纤维化，并缓解 MI 后 28 天的 LV 扩张和收缩功能障碍。M1 巨噬细胞和中性粒细胞是 IL-23 的主要细胞来源，而梗死心脏中超过 90%的 IL-17A 产生 T 细胞是 CD4(-)TCRγδ(+)（γδT）细胞。Toll 样受体信号和 IL-1β 与 IL-23 协同作用，驱动心脏 γδT 细胞的扩增和 IL-17A 产生，而鞘氨醇-1-磷酸受体和 CCL20/CCR6 信号通路介导 γδT 细胞募集到梗死心脏。IL-17A 不参与急性炎症反应，但它在晚期重构阶段特异性发挥作用，通过促进中性粒细胞和巨噬细胞的持续浸润，刺激巨噬细胞产生促炎细胞因子，加重心肌细胞死亡，并增强成纤维细胞增殖和促纤维化基因表达。
IL-23/IL-17A 免疫轴和 γδT 细胞是 MI 后预防进展为终末期扩张型心肌病的潜在有前途的治疗靶点。
