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Congenital Hepatic Fibrosis (CHF), a genetic disease caused by mutations in the PKHD1 gene, encoding for the protein fibrocystin (FPC), is characterized by biliary dysgenesis, progressive portal fibrosis, and by a PKA-mediated activating phosphorylation of β-Catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete CXCL10 a chemokine able to recruit macrophages. The aim of this study is to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/CD and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of Pkhd1del4/del4 mice for three-month with AMG-487, an inhibitor of CXCR3 the cognate receptor of CXCL10, reduces the peribiliary recruitment of M2 macrophages (CD45+ F4/80+ cells), spleen size, liver fibrosis (Sirius red), and cyst growth (K19+ area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in FPC-defective cholangiocytes, isolated from Pkhd1del4/del4 mice, CXCL10 production is mediated by JAK/STAT3, in response to IL-1β and β-Catenin. Specifically, IL-1β promotes STAT3 phosphorylation whereas β-Catenin promotes its nuclear translocation. Increased pro-IL-1β was regulated by NF-kB and increased secretion of active IL-1β was mediated by the activation of NLRP3 inflammasome (increased expression of caspase 1 and NLRP33)

Kaffe, E., Fiorotto, R., Pellegrino, F., Mariotti, V., Amenduni, M., Cadamuro, M., et al. (2018). β-catenin and IL-1β dependent CXCL10 production drives progression of disease in a mouse model of Congenital Hepatic Fibrosis. HEPATOLOGY, 67(5), 1903-1919 [10.1002/hep.29652].

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