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

Journal

Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946

Informations de publication

Date de publication:
02 Aug 2023
Historique:
received: 11 01 2023
accepted: 29 06 2023
medline: 3 8 2023
pubmed: 3 8 2023
entrez: 3 8 2023
Statut: aheadofprint

Résumé

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. 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 Kupffer cells, 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, 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 mAb-mediated neutralization of SPP1 confered 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 prognostic biomarker for liver transplant-free survival. Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as prognostic marker and future therapeutic target in PSC.

Sections du résumé

BACKGROUND AIMS UNASSIGNED
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 RESULTS UNASSIGNED
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 Kupffer cells, 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, 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 mAb-mediated neutralization of SPP1 confered 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 prognostic biomarker for liver transplant-free survival.
CONCLUSIONS CONCLUSIONS
Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as prognostic marker and future therapeutic target in PSC.

Identifiants

DOI: 10.1097/HEP.0000000000000557 PMID: 37535809
pubmed: 37535809
doi: 10.1097/HEP.0000000000000557
pii: 01515467-990000000-00520
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 American Association for the Study of Liver Diseases.

Auteurs

Kevin De Muynck (K)

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.

Lander Heyerick (L)

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.

Federico F De Ponti (FF)

Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.

Bart Vanderborght (B)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.

Tim Meese (T)

Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, 9000 Belgium.
NXTGNT, Ghent University, Ghent, 9000 Belgium.

Sanne Van Campenhout (S)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.

Leen Baudonck (L)

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.

Eva Gijbels (E)

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel (VUB), Brussels, 1000 Belgium.

Pedro M Rodrigues (PM)

Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain.
CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.

Jesus M Banales (JM)

Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain.
CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.

Mette Vesterhuus (M)

Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Department of Clinical Science, University of Bergen, Bergen, Norway.

Trine Folseraas (T)

Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Norway.
Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Charlotte L Scott (CL)

Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.

Mathieu Vinken (M)

Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel (VUB), Brussels, 1000 Belgium.

Malaïka Van der Linden (M)

Department of Pathology, Ghent University Hospital, Ghent, Belgium.

Anne Hoorens (A)

Department of Pathology, Ghent University Hospital, Ghent, Belgium.

Jo Van Dorpe (J)

Department of Pathology, Ghent University Hospital, Ghent, Belgium.

Sander Lefere (S)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.

Anja Geerts (A)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.
Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.

Filip Van Nieuwerburgh (F)

Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, 9000 Belgium.
NXTGNT, Ghent University, Ghent, 9000 Belgium.

Xavier Verhelst (X)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.
Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.

Hans Van Vlierberghe (H)

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium.
Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.

Lindsey Devisscher (L)

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.

Classifications MeSH