Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis
Open accessAbstract
Studies have suggested the reversibility of liver fibrosis, but the mechanisms of fibrosis reversal are poorly understood. We investigated the possible functional link between apoptosis, macrophages, and matrix turnover in rat liver during reversal of fibrosis secondary to bile duct ligation (BDL). Biliary fibrosis was induced by BDL for 4 wk. After Roux-en-Y (RY)-bilio-jejunal-anastomosis, resolution of fibrosis was monitored for up to 12 wk by hepatic collagen content, matrix metalloproteinase (MMP) expression and activities, and fibrosis-related gene expression. MMP expression and activities were studied in macrophages after engulfment of apoptotic cholangiocytes in vitro. Hepatic collagen decreased to near normal at 12 wk after RY-anastomosis. During reversal, profibrogenic mRNA declined, whereas expression of several profibrolytic MMPs increased. Fibrotic septa showed fragmentation at week 4 and disappeared at week 12. Peak histological remodeling at week 4 was characterized by massive apoptosis of cytokeratin 19+ cholangiocytes, >90% in colocalization with CD68+ macrophages, and a 2- to 7.5-fold increase in matrix-degrading activities. In vitro, phagocytosis of apoptotic cholangiocytes induced matrix-degrading activities and MMP-3, -8, and -9 in rat peritoneal macrophages. We concluded that reconstruction of bile flow after BDL leads to an orchestrated fibrolytic program that results in near complete reversal of advanced fibrosis. The peak of connective tissue remodeling and fibrolytic activity is associated with massive apoptosis of cholangiocytes and their phagocytic clearance by macrophages in vivo. Macrophages upregulate MMPs and become fibrolytic effector cells upon apoptotic cholangiocyte engulfment in vitro, suggesting that phagocytosis-associated MMP induction in macrophages significantly contributes to biliary fibrosis reversal.
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In a rat model of surgical recovery from bile duct ligation-induced fibrosis, phagocytic macrophages promote biliary fibrosis reversal via release of pro-fibrolytic MMPs upon engulfment of apoptotic cholangiocytes.
“Using an experimental model of surgical recovery from bile duct ligation-induced fibrosis in rats, we have previously observed that phagocytic macrophages promote (biliary) fibrosis reversal via the release of pro-fibrolytic MMPs upon engulfment of apoptotic cholangiocytes19.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [19]
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“Cholangiocyte apoptosis triggers recruitment of CD68 macrophages into scarred portal tracts to remove apoptotic cholangiocytes via phagocytosis (6) and to upregulate MMP-3, -8, and-9 to remodel the scar, leading to dissolution of fibrous septa and restoration of normal liver architecture.”
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- Authors
- Popov, Y., Sverdlov, D. Y., Bhaskar, K. R., Sharma, A. K., Millonig, G., Patsenker, E., Krahenbuhl, S., Krahenbuhl, L., & Schuppan, D.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University of Bern (CH)
- Department of Clinical Pharmacology & Toxicology and Research, University Hospital Basel;
- Department of Surgery, Hôpital Cantonal Fribourg, Switzerland
- Corresponding author
- Schuppan, Detlef
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2010-03
- Volume
- 298
- Issue
- 3
- Pages
- G323-G334
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- PMC
- PMC2838516
- OpenAlex
- W2020977337
- Cited by
- 136
- References
- 3
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 11 · 2019: 9 · 2018: 6 · 2017: 14 · 2016: 5 · 2015: 10 · 2014: 8 · 2013: 6 · 2012: 13
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK076873)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- biliary fibrosis, fibrosis reversal, macrophages, phagocytosis, matrix metalloproteinases, bile duct ligation, collagen deposition, hepatic stellate cells, cytokeratin 19, CD68, liver fibrosis
- MeSH terms
- Collagen Type I, alpha 1 Chain, Anastomosis, Roux-en-Y, Animals, Bile Ducts, Intrahepatic, Cell Line, Cell Movement, Cells, Cultured, Collagen, Ligation, Liver, Liver Cirrhosis, Biliary, Liver Cirrhosis, Experimental, Macrophages, Male, Models, Biological, Phagocytosis, Down-Regulation, Gene Expression, Transforming Growth Factor beta, Rats, Sprague-Dawley, Apoptosis, Collagenases, Plasminogen Activator Inhibitor 1, Bile Ducts, Extrahepatic, Gelatinases, Tissue Inhibitor of Metalloproteinase-1, Matrix Metalloproteinases, Collagen Type I, Integrin beta Chains, Mice, Rats
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