| Autor: |
Mederacke, Ingmar, Filliol, Aveline, Affo, Silvia, Nair, Ajay, Hernandez, Celine, Sun, Qiuyan, Hamberger, Florian, Brundu, Francesco, Chen, Yu, Ravichandra, Aashreya, Huebener, Peter, Anke, Helena, Shi, Hongxue, Martínez García de la Torre, Raquel A., Smith, James R., Henderson, Neil C., Vondran, Florian W. R., Rothlin, Carla V., Baehre, Heike, Tabas, Ira |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 4/6/2022, Vol. 14 Issue 639, p1-11, 11p |
| Abstrakt: |
Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor–β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5′-diphosphate (UDP)–glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal–regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis. A cell death-induced profibrotic signal: Dying hepatocytes are known to release so-called danger signals that promote fibrosis in hepatic stellate cells (HSCs), a central fibrogenic cell type in the liver. Mederacke et al. identified two nucleotide sugar compounds released by dead murine hepatocytes that signal danger within the liver by activating purinergic receptor P2Y14 in HSCs, inducing a profibrotic response. Knocking out this receptor abrogated liver fibrosis in mouse models of liver injury. P2Y14 was functionally expressed on human HSCs and increased in clinical cirrhotic liver samples, indicating that this ligand-receptor interaction may also promote fibrosis in humans. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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