The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction.
The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction.
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DOI：
10.1172/jci97192
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发表时间：
2018-08-01
期刊：
影响因子：
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通讯作者：
Riley PR
中科院分区：
文献类型：
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作者：
Vieira JM;Norman S;Villa Del Campo C;Cahill TJ;Barnette DN;Gunadasa-Rohling M;Johnson LA;Greaves DR;Carr CA;Jackson DG;Riley PR
冠脉循环阻塞引起的心肌梗死(MI)会导致大量的心肌细胞丢失，并被非收缩的瘢痕组织取代，导致病理性重构、功能障碍，最终导致心力衰竭。这目前是一个全球性的健康问题，目前还没有有效的治疗方法。心肌梗死后，先天免疫系统引导死亡细胞碎片的吞噬，以努力刺激细胞重新繁殖和组织更新。然而，在哺乳动物的成年心脏中，免疫细胞的持续涌入，加上缺乏固有的再生能力，导致了心脏纤维化。在这里，我们揭示，血管内皮生长因子-C刺激心脏淋巴管生成，通过依赖淋巴管内皮细胞透明质酸受体1(LYVE-1)的过程，将免疫细胞输送到引流纵隔淋巴结(MLN)，从而改善MI后急性炎症反应的清除。在小鼠中，LYVE1的缺失阻止了白细胞通过淋巴管内皮细胞的对接和转运，导致慢性炎症的加剧和心功能的长期恶化。我们的发现支持将淋巴/免疫细胞轴作为促进免疫调节和心脏修复的治疗范例。
Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.