Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation.
Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation.
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DOI：
10.1172/jci140685
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Thorp, Edward B.
中科院分区：
文献类型：
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作者：
Glinton, Kristofor E.;Ma, Wanshu;Lantz, Connor;Grigoryeva, Lubov S.;DeBerge, Matthew;Liu, Xiaolei;Febbraio, Maria;Kahn, Mark;Oliver, Guillermo;Thorp, Edward B.
心肌梗死（MI）后的心脏修复必须通过efferocytosis清除死亡细胞。最近的报道表明，血管内皮生长因子C （VEGFC）在心肌梗死后急性心肌淋巴管生成过程中具有保护作用。在这里，我们报道了实验性心肌梗死后巨噬细胞的efferocytosis缺陷导致心肌淋巴管生成和VEGFC表达减少。在培养的原代巨噬细胞中加入凋亡细胞，随后触发Vegfc转录和Vegfc分泌，揭示了Vegfc诱导成efferocytic的细胞内在证据。类似地，心肌巨噬细胞在心肌梗死后Vegfc表达水平升高，骨髓性Vegfc缺乏的小鼠表现出心室收缩性受损、不良组织重塑和淋巴管生成减少。这些结果在小鼠永久性冠状动脉闭塞和临床相关的缺血再灌注模型中观察到。有趣的是，髓系Vegfc缺乏也导致急性梗死面积的增加，在急性心脏淋巴管生成反应的振幅之前。RNA-Seq和心脏流式细胞术显示，骨髓性Vegfc缺乏也以炎症反应缺陷为特征，巨噬细胞产生的Vegfc直接有效地抑制促炎巨噬细胞的激活。综上所述，我们的研究结果表明，心脏巨噬细胞通过促进心肌淋巴管生成和抑制炎症细胞因子来促进愈合。
Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.