Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells

Frontiers in Immunology

Jay R. Hesselberth¹  Ronald P. Schuyler²  Jeffrey M. Finlon³  Michael S. Kriss³  Hugo R. Rosen⁴  Matthew A. Burchill⁵  Beth A. Jiron Tamburini⁵  Rui Fu⁵  Austin E. Gillen⁵  Kent A. Riemondy⁵ 

[1] Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO, United States;Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, United States;Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, United States;Keck School of Medicine, University of Southern California, Los Angeles, CA, United States;RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States;

关键词: lymphatic endothelial cells;    cirrhosis;    fibrosis;    non-alcoholic steatohepatitis;    hepatitis C virus;    alcoholic liver disease;   

DOI  :  10.3389/fimmu.2019.01036

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown