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
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Medientyp:
E-Artikel
Titel:
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
Erschienen in:
Hepatology, 67 (2018) 5, Seite 1903-1919
Sprache:
Englisch
DOI:
10.1002/hep.29652
ISSN:
0270-9139;
1527-3350
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>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 <jats:italic toggle="yes">Pkhd1del4/del4
</jats:italic> 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 <jats:italic toggle="yes">Pkhd1del4/del4
</jats:italic> 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<jats:sup>+</jats:sup>F4/80<jats:sup>+</jats:sup> 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 <jats:italic toggle="yes">Pkhd1del4/del4
</jats:italic> 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). <jats:italic toggle="yes">Conclusion:</jats:italic> 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; <jats:italic toggle="yes">in vivo</jats:italic> 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<jats:sc>epatology</jats:sc> 2018;67:1903‐1919).</jats:p>