Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing 100037, China.
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou 510080, China.
Cardiovasc Res. 2022 Jul 20;118(9):2165-2178. doi: 10.1093/cvr/cvab237.
Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.
MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.
IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.
白细胞介素（IL）-5 介导嗜酸性粒细胞（EOS）的发育，EOS 对于组织损伤后修复至关重要。目前尚不清楚 IL-5 在心肌梗死后（MI）的心脏修复中是否发挥作用。本研究旨在检验 IL-5 诱导的 EOS 群体是否促进 MI 后愈合和修复过程，并揭示潜在的机制。
通过结扎左前降支冠状动脉永久性结扎在野生型 C57BL/6 小鼠中诱导 MI。Western blot 和实时聚合酶链反应显示 MI 后 5 天心脏中 IL-5 的表达升高。免疫组织化学染色表明，在实验性 MI 中，IL-5 主要由巨噬细胞和 CD127+细胞分泌。重组鼠 IL-5（MI 手术后 20 分钟、1 天和 2 天）的外源性供应减少了梗死面积并增加了边缘带的射血分数和血管生成。在给予 IL-5 后，外周血和梗死心肌中均检测到 EOS 的显著扩张。TRFK5 预处理耗尽 EOS 可减弱 IL-5 在 MI 小鼠中的有益作用。机制研究表明，IL-5 在 MI 后 7 天增加了梗死心肌中 CD206+巨噬细胞的积累。体外共培养实验表明，EOS 将骨髓来源的巨噬细胞向 CD206+表型极化。这种 EOS 活性被 IL-4 中和抗体消除，但不能被 IL-10 或 IL-13 中和抗体消除。Western blot 分析表明，EOS 通过 IL-4/STAT6 轴促进巨噬细胞下游信号转导和转录激活因子 6（STAT6）磷酸化。
IL-5 通过促进 EOS 积累和随后的 CD206+巨噬细胞极化，促进 MI 后心脏功能障碍的恢复，这是通过 IL-4/STAT6 轴实现的。
