Premium
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
Author(s) -
Kaffe Eleanna,
Fiorotto Romina,
Pellegrino Francesca,
Mariotti Valeria,
Amenduni Mariangela,
Cadamuro Massimiliano,
Fabris Luca,
Strazzabosco Mario,
Spirli Carlo
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29652
Subject(s) - cxcl10 , biology , cancer research , chemokine , stat protein , microbiology and biotechnology , signal transduction , endocrinology , medicine , immunology , stat3 , inflammation
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 Pkhd1 del4/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 Pkhd1 del4/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 Pkhd1 del4/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. (H epatology 2018;67:1903‐1919).