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dc.contributor.authorDe Muynck, Kevin
dc.contributor.authorHeyerick, Lander
dc.contributor.authorDe Ponti, Federico F.
dc.contributor.authorVanderborght, Bart
dc.contributor.authorMeese, Tim
dc.contributor.authorVan Campenhout, Sanne
dc.contributor.authorBaudonck, Leen
dc.contributor.authorGijbels, Eva
dc.contributor.authorRodrigues, Pedro M.
dc.contributor.authorBanales, Jesus M.
dc.contributor.authorVesterhus, Mette Nåmdal
dc.contributor.authorFolseraas, Trine
dc.contributor.authorScott, Charlotte L.
dc.contributor.authorVinken, Mathieu
dc.contributor.authorVan Der Linden, Malaïka
dc.contributor.authorHoorens, Anne
dc.contributor.authorVan Dorpe, Jo
dc.contributor.authorLefere, Sander
dc.contributor.authorGeerts, Anja
dc.contributor.authorVan Nieuwerburgh, Filip
dc.contributor.authorVerhelst, Xavier
dc.contributor.authorVan Vlierberghe, Hans
dc.contributor.authorDevisscher, Lindsey
dc.date.accessioned2024-09-12T10:37:49Z
dc.date.available2024-09-12T10:37:49Z
dc.date.created2024-02-21T07:33:26Z
dc.date.issued2024
dc.identifier.issn0270-9139
dc.identifier.urihttps://hdl.handle.net/11250/3151731
dc.description.abstractBackground 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.en_US
dc.language.isoengen_US
dc.publisherWolters Kluweren_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/deed.no*
dc.titleOsteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitisen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2023 The Author(s)en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2
dc.identifier.doi10.1097/HEP.0000000000000557
dc.identifier.cristin2248250
dc.source.journalHepatologyen_US
dc.source.pagenumber269-288en_US
dc.identifier.citationHepatology. 2024, 79 (2), 269-288.en_US
dc.source.volume79en_US
dc.source.issue2en_US


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Attribution-NonCommercial-NoDerivatives 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 Internasjonal