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CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis

ABSTRACT: CCL24 is a profibrotic, proinflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Mdr2-/- mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24 neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under profibrotic conditions in primary human cholangiocytes and macrophages and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of PSC patients. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in PSC patients via reduced liver inflammation, fibrosis and cholestasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE228596 | GEO | 2023/04/30

REPOSITORIES: GEO

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STAT3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis

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2022-08-03 | PXD026694 | Pride

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2022-08-03 | PXD026693 | Pride

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Project description:Background & Aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Here, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods: levels and function of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results: most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered the proteasome hyperactivity in cystic cholangiocytes, leading to the activation the unfolded protein response (UPR) and stress-related apoptosis.

2020-09-29 | PXD021140 | Pride

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2020-09-29 | PXD021139 | Pride

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