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

(2024) HEPATOLOGY. 79(2). p.269-288
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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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MLA
De Muynck, Kevin, et al. “Osteopontin Characterizes Bile Duct-Associated Macrophages and Correlates with Liver Fibrosis Severity in Primary Sclerosing Cholangitis.” HEPATOLOGY, vol. 79, no. 2, 2024, pp. 269–88, doi:10.1097/HEP.0000000000000557.
APA
De Muynck, K., Heyerick, L., De Ponti, F. F., Vanderborght, B., Meese, T., Van Campenhout, S., … Devisscher, L. (2024). Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis. HEPATOLOGY, 79(2), 269–288. https://doi.org/10.1097/HEP.0000000000000557
Chicago author-date
De Muynck, Kevin, Lander Heyerick, Federico Francesco De Ponti, Bart Vanderborght, Tim Meese, Sanne Van Campenhout, Leen Baudonck, et al. 2024. “Osteopontin Characterizes Bile Duct-Associated Macrophages and Correlates with Liver Fibrosis Severity in Primary Sclerosing Cholangitis.” HEPATOLOGY 79 (2): 269–88. https://doi.org/10.1097/HEP.0000000000000557.
Chicago author-date (all authors)
De Muynck, Kevin, Lander Heyerick, Federico Francesco De Ponti, Bart Vanderborght, Tim Meese, Sanne Van Campenhout, Leen Baudonck, Eva Gijbels, Pedro M. Rodrigues, Jesus M. Banales, Mette Vesterhuus, Trine Folseraas, Charlotte Scott, Mathieu Vinken, Malaïka Van der Linden, Anne Hoorens, Jo Van Dorpe, Sander Lefere, Anja Geerts, Filip Van Nieuwerburgh, Xavier Verhelst, Hans Van Vlierberghe, and Lindsey Devisscher. 2024. “Osteopontin Characterizes Bile Duct-Associated Macrophages and Correlates with Liver Fibrosis Severity in Primary Sclerosing Cholangitis.” HEPATOLOGY 79 (2): 269–288. doi:10.1097/HEP.0000000000000557.
Vancouver
1.
De Muynck K, Heyerick L, De Ponti FF, Vanderborght B, Meese T, Van Campenhout S, et al. Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis. HEPATOLOGY. 2024;79(2):269–88.
IEEE
[1]
K. De Muynck et al., “Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis,” HEPATOLOGY, vol. 79, no. 2, pp. 269–288, 2024.
@article{01HMBQ7JC79F1B8RA8PM70YMS1,
  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.}},
  author       = {{De Muynck, Kevin and Heyerick, Lander and De Ponti, Federico Francesco and Vanderborght, Bart and Meese, Tim and Van Campenhout, Sanne and Baudonck, Leen and Gijbels, Eva and  Rodrigues, Pedro M. and  Banales, Jesus M. and  Vesterhuus, Mette and  Folseraas, Trine and Scott, Charlotte and  Vinken, Mathieu and Van der Linden, Malaïka and Hoorens, Anne and Van Dorpe, Jo and Lefere, Sander and Geerts, Anja and Van Nieuwerburgh, Filip and Verhelst, Xavier and Van Vlierberghe, Hans and Devisscher, Lindsey}},
  issn         = {{0270-9139}},
  journal      = {{HEPATOLOGY}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{269--288}},
  title        = {{Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis}},
  url          = {{http://doi.org/10.1097/HEP.0000000000000557}},
  volume       = {{79}},
  year         = {{2024}},
}

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