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Updated: Feb 10, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice
Maria Eugenia Guicciardi1, Christy E Trussoni1, Anuradha Krishnan1
1Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Rochester, MN, USA.
Background & Aims:
Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC.
Methods:
Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the inhibitor of apoptosis antagonist BV6) and chronic (Mdr2-/- mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from patients with PSC. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2-/- mice) were determined in BV6-injected mice.
Results:
We found increased peribiliary pro-inflammatory (M1-like) and alternatively-activated (M2-like) monocyte-derived macrophages in PSC compared to normal livers. In both SC models, genetic profiling of liver immune cells identified a predominance of monocytes/macrophages; immunohistochemistry confirmed peribiliary monocyte-derived macrophage recruitment (M1>M2-polarized), which paralleled injury onset and was reversed upon resolution in acute SC mice. PSC, senescent and BV6-treated human cholangiocytes released monocyte chemoattractants (CCL2, IL-8) and macrophage-activating factors in vitro. Pharmacological inhibition of monocyte recruitment by CVC treatment or CCR2 genetic deletion attenuated macrophage accumulation, liver injury and fibrosis in acute SC.
Conclusions:
Peribiliary recruited macrophages are a feature of both PSC and acute and chronic murine SC models. Pharmacologic and genetic inhibition of peribiliary macrophage recruitment decreases liver injury and fibrosis in mouse SC. These observations suggest monocyte-derived macrophages contribute to the development of SC in mice and in PSC pathogenesis, and support their potential as a therapeutic target.
Lay Summary:
Primary sclerosing cholangitis (PSC) is an inflammatory liver disease which often progresses to liver failure. The cause of the disease is unclear and therapeutic options are limited. Therefore, we explored the role of white blood cells termed macrophages in PSC given their frequent contribution to other human inflammatory diseases. Our results implicate macrophages in PSC and PSC-like diseases in mice. More importantly, we found that pharmacologic inhibition of macrophage recruitment to the liver reduces PSC-like liver injury in the mouse. These exciting observations highlight potential new strategies to treat PSC.
Insights
Macrophages play a key role in primary sclerosing cholangitis (PSC) liver disease. Inhibiting macrophage recruitment to the liver reduced liver injury and fibrosis in mouse models, suggesting a potential new therapeutic strategy for PSC.
Area of Science:
- Hepatology and Immunology
- Liver Disease Pathogenesis
- Cholestatic Liver Injury
Background:
- Macrophages are implicated in liver disease, but their specific role in cholestatic conditions like primary sclerosing cholangitis (PSC) remains unclear.
- Understanding macrophage involvement is crucial for developing targeted therapies for PSC, an inflammatory liver disease with limited treatment options.
Purpose of the Study:
- To investigate the hypothesis that macrophages contribute to the pathogenesis of PSC.
- To evaluate macrophages as potential therapeutic targets for PSC and related sclerosing cholangitis (SC) models.
Main Methods:
- Utilized acute (BV6 injection) and chronic (Mdr2-/- mice) mouse models of sclerosing cholangitis (SC).
- Assessed immune cell profiles, macrophage characteristics (number, localization, polarization), fibrosis, and liver injury markers.
- Investigated therapeutic effects of CCR2/5 antagonist cenicriviroc (CVC) and CCR2 genetic deletion (Ccr2-/- mice).
Main Results:
- Increased peribiliary M1 and M2-like monocyte-derived macrophages were observed in SC models and human PSC liver samples.
- Macrophage recruitment correlated with liver injury onset and was reversible in acute SC models.
- Inhibition of monocyte recruitment via CVC or CCR2 deletion significantly reduced macrophage accumulation, liver injury, and fibrosis in mice.
Conclusions:
- Peribiliary macrophages are a characteristic feature of PSC and murine SC models.
- Inhibiting macrophage recruitment effectively decreases liver injury and fibrosis in experimental SC.
- Monocyte-derived macrophages are integral to SC pathogenesis, highlighting their potential as a therapeutic target for PSC.
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