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].
Citazione: | 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]. | |
Tipo: | Articolo in rivista - Articolo scientifico | |
Carattere della pubblicazione: | Scientifica | |
Presenza di un coautore afferente ad Istituzioni straniere: | Si | |
Titolo: | β-catenin and IL-1β dependent CXCL10 production drives progression of disease in a mouse model of Congenital Hepatic Fibrosis | |
Autori: | Kaffe, E; Fiorotto, R; Pellegrino, F; Mariotti, V; Amenduni, M; Cadamuro, M; Fabris, L; Strazzabosco, M; Spirli, C | |
Autori: | ||
Data di pubblicazione: | 2018 | |
Lingua: | English | |
Rivista: | HEPATOLOGY | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1002/hep.29652 | |
Appare nelle tipologie: | 01 - Articolo su rivista |