EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization. Issue 9 (10th August 2021)

• Record Type: Journal Article
• Authors: Wei, Xiaoqiong; Zou, Song; Xie, Zhonghui; Wang, Zhen; Huang, Nongyu; Cen, Zhifu; Hao, Yan; Zhang, Chengxin; Chen, Zhenyu; Zhao, Fulei; Hu, Zhonglan; Teng, Xiu; Gui, Yiyue; Liu, Xiao; Zheng, Huaping; Zhou, Hong; Chen, Shuwen; Cheng, Juan; Zeng, Fanlian; Zhou, Yifan; Wu, Wenling; Hu, Jing; Wei, Yuquan; Cui, Kaijun; Li, Jiong
• Is Part Of: Cardiovascular research. Volume 118:Issue 9(2022)
• Page Start: 2179
• Page End: 2195
• Publication Date: 2021-08-10
• Subjects: NETs -- Myocardial infarction -- Macrophages -- EDIL3 -- Fibrosis; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvab269
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. Methods and results: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3 −/− mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3 − / − mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk − MHC-II lo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3 − / − mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3 − / − mice, contributed to Mertk − MHC-II lo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3 − / − mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. Conclusion: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI. Graphical abstract: