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

Revised Passage:

Congenital hepatic fibrosis (CHF) is a genetic disorder caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which encodes the fibrocystin/polyductin complex. This condition is characterized by biliary dysgenesis, progressive portal fibrosis, and protein kinase A-mediated phosphorylation of β-catenin at Ser675. In a mouse model of CHF (Pkhd1^del4/del4^), biliary structures secrete chemokine (C-X-C motif) ligand 10 (CXCL10), a molecule known to recruit macrophages. This study aimed to investigate the pathogenetic role of CXCL10 in the progression of CHF and Caroli disease, as well as the mechanisms driving its increased secretion.

The results demonstrate that treating Pkhd1^del4/del4^ mice with AMG-487, an inhibitor of CXC chemokine receptor 3 (the receptor for CXCL10), for three months reduces peribiliary recruitment of alternatively activated macrophages (CD45^+^ F4/80^+^ cells), spleen size, liver fibrosis (as assessed by Sirius Red staining), and cyst growth (cytokeratin 19-positive area). These findings support a pathogenetic role for CXCL10 in CHF. Additionally, in fibrocystin/polyductin-defective cholangiocytes isolated from Pkhd1^del4/del4^ mice, CXCL10 production is mediated by the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in response to interleukin-1β (IL-1β) and β-catenin signaling. Specifically, IL-1β induces STAT3 phosphorylation, while β-catenin facilitates its nuclear translocation. Pro-IL-1β expression is regulated by nuclear factor kappa B (NF-κB), and the secretion of active IL-1β is driven by Nod-like receptor AMG 487 protein 3 (NLRP3) inflammasome activation, which includes increased expression of caspase-1 and NLRP3.

Conclusion: In fibrocystin/polyductin-defective cholangiocytes, β-catenin and IL-1β drive STAT3-dependent CXCL10 secretion. In vivo findings reveal that the CXCL10/CXC chemokine receptor 3 axis contributes to macrophage recruitment, inflammation, and disease progression. Furthermore, the increased production of IL-1β underscores the autoinflammatory nature of CHF, offering potential targets for novel therapeutic strategies. (Hepatology 2018;67:1903-1919)