β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis

• Published in: Hepatology (Baltimore, Md.) Vol. 67; no. 5; pp. 1903 - 1919
• Main Authors: Kaffe, Eleanna, Fiorotto, Romina, Pellegrino, Francesca, Mariotti, Valeria, Amenduni, Mariangela, Cadamuro, Massimiliano, Fabris, Luca, Strazzabosco, Mario, Spirli, Carlo
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2018
• Subjects: Animals; beta Catenin - metabolism; Blotting, Western; Caspase; Caspase-1; Catenin; Chemokine CXCL10 - metabolism; Chemokines; Congenital diseases; CXC chemokines; CXCL10 protein; Cytokeratin; Cytokines; Disease Models, Animal; Disease Progression; Epithelial Cells - metabolism; Fibrosis; Flow Cytometry; Genetic Diseases, Inborn - metabolism; Hepatocytes; Hepatology; IL-1β; Immunohistochemistry; Inflammasomes; Interleukin-1beta - metabolism; Janus kinase; Kinases; Ligands; Liver - metabolism; Liver - pathology; Liver Cirrhosis - metabolism; Liver diseases; Lymphocytes B; Macrophages; Mice; Mutation; Nuclear transport; Phosphorylation; Polycystic kidney; Protein kinase A; Pyrin protein; Real-Time Polymerase Chain Reaction; Receptors, CXCR3 - metabolism; Signal Transduction; Spleen; Transcription
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.29652

Congenital hepatic fibrosis (CHF), a genetic disease caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, encoding for the protein fibrocystin/polyductin complex, is characterized by biliary dysgenesis, progressive portal fibrosis, and a protein kinase A–mediated activating phosphorylation of β‐catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete chemokine (C‐X‐C motif) ligand 10 (CXCL10), a chemokine able to recruit macrophages. The aim of this study was to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/Caroli disease and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of Pkhd1del4/del4 mice for 3 months with AMG‐487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45+F4/80+ cells), spleen size, liver fibrosis (sirius red), and cyst growth (cytokeratin 19–positive area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in fibrocystin/polyductin complex–defective cholangiocytes, isolated from Pkhd1del4/del4 mice, CXCL10 production is mediated by Janus kinase/signal transducer and activator of transcription 3 in response to interleukin 1beta (IL‐1β) and β‐catenin. Specifically, IL‐1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β‐catenin promotes its nuclear translocation. Increased pro‐IL‐1β was regulated by nuclear factor kappa‐light‐chain‐enhancer of activated B cells, and increased secretion of active IL‐1β was mediated by the activation of Nod‐like receptors, pyrin domain containing 3 inflammasome (increased expression of caspase 1 and Nod‐like receptors, pyrin domain containing 3). Conclusion: In fibrocystin/polyductin complex–defective cholangiocytes, β‐catenin and IL‐1β are responsible for signal transducer and activator of transcription 3–dependent secretion of CXCL10; in vivo experiments show that the CXCL10/CXC chemokine receptor family 3 axis prevents the recruitment of macrophages, reduces inflammation, and halts the progression of the disease; the increased production of IL‐1β highlights the autoinflammatory nature of CHF and may open novel therapeutic avenues. (Hepatology 2018;67:1903‐1919).