2. Academic Validation
  3. Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

  • Hepatology. 2024 Feb 1;79(2):269-288. doi: 10.1097/HEP.0000000000000557.
Kevin De Muynck 1 2,  Lander Heyerick 1 2,  Federico F De Ponti 3 4,  Bart Vanderborght 2 5,  Tim Meese 6 7,  Sanne Van Campenhout 2 5,  Leen Baudonck 1,  Eva Gijbels 1 8,  Pedro M Rodrigues 9 10 11,  Jesus M Banales 9 10 11 12,  Mette Vesterhuus 13 14,  Trine Folseraas 13 15 16,  Charlotte L Scott 3 4,  Mathieu Vinken 8,  Malaïka Van der Linden 17,  Anne Hoorens 17,  Jo Van Dorpe 17,  Sander Lefere 2 5,  Anja Geerts 2 5 18,  Filip Van Nieuwerburgh 6 7,  Xavier Verhelst 2 5 18,  Hans Van Vlierberghe 2 5 18,  Lindsey Devisscher 1 2
Affiliations

Affiliations

  • 1 Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
  • 2 Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
  • 3 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 4 Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
  • 5 Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.
  • 6 Department of Pharmaceutics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
  • 7 NXTGNT, Ghent University, Ghent, Belgium.
  • 8 Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • 9 Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain.
  • 10 CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • 11 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
  • 12 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
  • 13 Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Norwegian PSC Research Center, Oslo, Norway.
  • 14 Department of Clinical Science, University of Bergen, Bergen, Norway.
  • 15 Institute of Clinical Medicine, University of Oslo, Norway.
  • 16 Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
  • 17 Department of Pathology, Ghent University Hospital, Ghent, Belgium.
  • 18 Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.
PMID: 37535809 DOI: 10.1097/HEP.0000000000000557
Abstract

Background and aims: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood.

Approach and results: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 ( Trem2 ) and Osteopontin ( Spp1 ), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF- Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro , while monoclonal antibody-mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum Osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival.

Conclusions: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.

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