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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.

ABSTRACT: 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 Pkhd1del4/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 Pkhd1del4/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 Pkhd1del4/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. (Hepatology 2018;67:1903-1919).

SUBMITTER: Kaffe E

PROVIDER: S-EPMC5906178 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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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.

Kaffe Eleanna E Fiorotto Romina R Pellegrino Francesca F Mariotti Valeria V Amenduni Mariangela M Cadamuro Massimiliano M Fabris Luca L Strazzabosco Mario M Spirli Carlo C

Hepatology (Baltimore, Md.) 20180325 5

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<sup>del4/del4</sup> mice, a mouse model of CHF, secrete chemokine (C-X-C motif) ligand 10 (CXCL10), a chemokine able to recruit m ...[more]

PMID: 29140564

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Project description:BackgroundAlthough programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment.MethodsWe prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition.ResultsThe baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs.ConclusionsPlasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

Project description:Background and aimsDuring liver fibrosis, liver sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory cells into the liver. p300, a master regulator of gene transcription, is associated with pathological inflammatory response. Therefore, we examined how endothelial p300 regulates angiocrine signaling and inflammation related to portal hypertension and fibrogenesis.Approach and resultsCCl4 or partial inferior vena cava ligation (pIVCL) was used to induce liver injury. Mice with LSEC-specific p300 deletion (p300LSECΔ/Δ ) or C-C motif chemokine ligand 2 (Ccl2) deficiency, nuclear factor kappa B (NFκB)-p50 knockout mice, and bromodomain containing 4 (BRD4) inhibitors in wild-type mice were used to investigate mechanisms of inflammation regulation. Leukocytes were analyzed by mass cytometry by time-of-flight. Epigenetic histone marks were modified by CRISPR endonuclease-deficient CRISPR-associated 9-fused with the Krüppel associated box domain (CRISPR-dCas9-KRAB)-mediated epigenome editing. Portal pressure and liver fibrosis were reduced in p300LSECΔ/Δ mice compared to p300fl/fl mice following liver injury. Accumulation of macrophages was also reduced in p300LSECΔ/Δ mouse livers. Ccl2 was the most up-regulated chemokine in injured LSECs, but its increase was abrogated in p300LSECΔ/Δ mice. While the macrophage accumulation was increased in NFκB-p50 knockout mice with enhanced NFκB activity, it was reduced in mice with LSEC-specific Ccl2 deficiency and mice treated with specific BRD4 inhibitors. In vitro, epigenome editing of CCL2 enhancer and promoter regions by CRISPR-dCas9-KRAB technology repressed TNFα-induced CCL2 transcription through H3K9 trimethylation. In contrast, TNFα activated CCL2 transcription by promoting p300 interaction with NFκB and BRD4, leading to histone H3 lysine 27 acetylation at CCL2 enhancer and promoter regions.ConclusionsIn summary, endothelial p300 interaction with NFκB and BRD4 increases CCL2 expression, leading to macrophage accumulation, portal hypertension, and liver fibrosis. Inhibition of p300 and its binding partners might serve as therapy in the treatment of liver diseases.

Dataset Information

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.

Publications

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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