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Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis

  • Kevin De Muynck
    Affiliations
    Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
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  • Bart Vanderborght
    Affiliations
    Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
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  • Federico F. De Ponti
    Affiliations
    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
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  • Eva Gijbels
    Affiliations
    Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
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  • Sophie Van Welden
    Affiliations
    Inflammatory Bowel Disease Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
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  • Martin Guilliams
    Affiliations
    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium
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  • Charlotte L. Scott
    Affiliations
    Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium

    Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
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  • Alain Beschin
    Affiliations
    Cellular & Molecular Immunology Research Group, Vrije Universiteit Brussel, Brussels, Belgium

    Myeloid Cell Immunology Lab, VIB-VUB, Brussels, Belgium
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  • Mathieu Vinken
    Affiliations
    Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
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  • Sander Lefere
    Affiliations
    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
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  • Anja Geerts
    Affiliations
    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
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  • Xavier Verhelst
    Affiliations
    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
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  • Hans Van Vlierberghe
    Affiliations
    Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium

    Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
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  • Lindsey Devisscher
    Correspondence
    Address correspondence to Lindsey Devisscher, Campus UZ Ghent, Corneel Heymanslaan 10, Bldg. B, Entrance 36, B-9000 Ghent, Belgium.
    Affiliations
    Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium
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Published:January 12, 2023DOI:https://doi.org/10.1016/j.ajpath.2022.12.008
      Primary sclerosing cholangitis (PSC) is an idiopathic chronic immune-mediated cholestatic liver disease characterized by fibro-inflammatory bile duct strictures, progressive hepatobiliary fibrosis, and gut–liver axis disruption. The pathophysiology of PSC remains insufficiently characterized, which hampers the development of effective therapies. Hepatic macrophages (MFs) are implicated in PSC pathogenesis, but the exact role of Kupffer cells (KCs) is unclear. Using the latest markers to discriminate resident KCs (ResKCs) from their monocyte-derived counterparts (MoKCs), and two models for intrahepatic and extrahepatic cholestasis, respectively, this study shows that CLEC4F+TIM4+ ResKCs are depleted after chronic cholestatic liver injury, whereas infiltrating CLEC4F+TIM4 MoKCs are already enriched during the acute phase. Transcriptional profiling of hepatic MF subsets during early cholestatic injury indicates that ResKCs are indeed activated and that MoKCs express even higher levels of pro-inflammatory and proliferative markers compared with ResKCs. Conditional depletion of KCs, by using Clec4fDTR transgenic mice, before and during early cholestasis induction had no effect, however, on the composition of the hepatic myeloid cell pool following injury progression and did not affect disease outcomes. Taken together, these results provide new insights on the heterogeneity of the MF pool during experimental PSC and evidence that depletion of resident and activated KCs during sclerosing cholangitis does not affect disease outcome in mice.

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