Aims

We aimed to investigate the effect and mechanism of pleiotropic chemokine CCL24 in heart failure.

Methods and results

Compared with normal donators, the expression of CCL24 and number of cardiac M2 macrophages in heart were higher in heart failure patients, the same as plasma CCL24. Treatment with CCL24 antibody hindered Ang II (1500 ng/kg/min)–induced cardiac adverse remodeling through preventing cardiac hypertrophy and fibrosis. RNA-seq showed that CCL24/CCR3 axis was involved in immune and inflammatory responses. Single-cell analysis of cytometry by time of flight (CyTOF) revealed that CCL24 antibody decreased the M2 macrophage and monocyte polarization during Ang II stimulation. Immunofluorescence co-localization analysis confirmed the expression of CCR3 in macrophage and fibroblasts. Then, in vitro experiments confirmed that CCL24/CCR3 axis was also involved in cardiac primary fibroblast activation through its G protein–coupled receptor function.

Conclusion

CCL24/CCR3 axis plays a crucial part in cardiac remodeling by stimulating M2 macrophage polarization and cardiac fibroblast activation.

Graphical abstract

Cardiac M2 macrophages, CCL24 and circulation CCL24 increased in heart failure patients. Treatment with CCL24 Ab hindered Ang II induced cardiac structural dysfunction and electrical remodeling. In CCL24 Ab group RNA-seq found that it was related to immune responses and hypertrophic cardiomyopathy, CytoF revealed M2 macrophages and monocytes decreased obviously. In vitro,CCL24 promoted activation and migration of cardiac fibroblast.

中文翻译：

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CCL24/CCR3轴通过刺激M2巨噬细胞极化和成纤维细胞活化在血管紧张素II诱导的心力衰竭中发挥核心作用

目标

我们的目的是探讨多效趋化因子CCL24在心力衰竭中 的作用和机制。

方法和结果

与正常供者相比，心力衰竭患者心脏中CCL24的表达和心脏M2巨噬细胞的数量较高，与血浆CCL24相同。CCL24 抗体治疗可通过预防心脏肥大和纤维化来阻碍 Ang II (1500 ng/kg/min) 诱导的心脏不良重塑。RNA-seq显示CCL24/CCR3轴参与免疫和炎症反应。通过飞行时间 (CyTOF) 进行的细胞计数单细胞分析表明，CCL24 抗体可降低 Ang II 刺激期间的 M2 巨噬细胞和单核细胞极化。免疫荧光共定位分析证实了巨噬细胞和成纤维细胞中CCR3的表达。然后，体外实验证实CCL24 / CCR3轴也通过其G蛋白偶联受体功能参与心脏原代成纤维细胞活化。

结论

CCL24/CCR3轴通过刺激 M2 巨噬细胞极化和心脏成纤维细胞激活，在心脏重塑中发挥至关重要的作用。

图形概要

心力衰竭患者心脏 M2 巨噬细胞、CCL24 和循环 CCL24 增加。CCL24 Ab 治疗可阻碍 Ang II 诱导的心脏结构功能障碍和电重塑。CCL24 Ab组RNA-seq发现与免疫反应和肥厚性心肌病有关，CytoF显示M2巨噬细胞和单核细胞明显减少。在体外，CCL24促进心脏成纤维细胞的活化和迁移。