Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells
Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells
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DOI：
10.3389/fimmu.2019.01036
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发表时间：
2019-05-15
影响因子：
7.3
通讯作者：
Burchill, Matthew A.
中科院分区：
文献类型：
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作者：
Tamburini, Beth A. Jiron;Finlon, Jeffrey M.;Burchill, Matthew A.
肝淋巴管通过引流间质液、胆固醇、脂肪和监测肝引流淋巴结的免疫细胞来支持肝功能。慢性肝病与炎症和免疫细胞浸润增加有关。然而，目前尚不清楚在慢性疾病期间，淋巴管是否或如何对肝脏中增加的炎症和免疫细胞浸润作出反应。在这里，我们证明慢性肝病患者的淋巴管丰度增加，并与纤维化和免疫细胞浸润有关。通过单细胞mRNA测序和多光谱免疫荧光分析，我们确定了肝淋巴内皮细胞，发现慢性肝病导致淋巴内皮细胞（LECs）处于活跃的细胞周期，CCL21的表达增加。此外，我们发现来自NASH患者的LECs采用与IL13信号通路增加相关的转录程序。此外，我们发现与NASH发病机制相关的氧化低密度脂蛋白在体外和小鼠模型中诱导LECs中IL13的转录和蛋白质产生。最后，我们发现氧化的低密度脂蛋白降低了PROX1的转录并降低了淋巴稳定性。综上所述，这些数据表明LECs在肝脏中是活跃的参与者，通过扩张来维持组织稳态。然而，当炎症信号，如氧化低密度脂蛋白增加时，如NASH，淋巴功能下降，肝脏稳态受到阻碍。
Liver lymphatic vessels support liver function by draining interstitial fluid, cholesterol, fat, and immune cells for surveillance in the liver draining lymph node. Chronic liver disease is associated with increased inflammation and immune cell infiltrate. However, it is currently unknown if or how lymphatic vessels respond to increased inflammation and immune cell infiltrate in the liver during chronic disease. Here we demonstrate that lymphatic vessel abundance increases in patients with chronic liver disease and is associated with areas of fibrosis and immune cell infiltration. Using single-cell mRNA sequencing and multi-spectral immunofluorescence analysis we identified liver lymphatic endothelial cells and found that chronic liver disease results in lymphatic endothelial cells (LECs) that are in active cell cycle with increased expression of CCL21. Additionally, we found that LECs from patients with NASH adopt a transcriptional program associated with increased IL13 signaling. Moreover, we found that oxidized low density lipoprotein, associated with NASH pathogenesis, induced the transcription and protein production of IL13 in LECs both in vitro and in a mouse model. Finally, we show that oxidized low density lipoprotein reduced the transcription of PROX1 and decreased lymphatic stability. Together these data indicate that LECs are active participants in the liver, expanding in an attempt to maintain tissue homeostasis. However, when inflammatory signals, such as oxidized low density lipoprotein are increased, as in NASH, lymphatic function declines and liver homeostasis is impeded.