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Updated: May 24, 2026
Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans
Charalambos Gustav Antoniades1, Alberto Quaglia, Leonie S Taams
1Institute of Liver Studies and Cellular Biology of Inflammation, King's College London, London, United Kingdom. c.antoniades@imperial.ac.uk
Unlabelled:
Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls.
Conclusion:
In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.
Insights
In acetaminophen-induced acute liver failure (AALF), hepatic macrophages expand via proliferation and monocyte recruitment. These macrophages, found in a regenerative environment, suggest a role in resolving inflammation and repairing liver tissue.
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- Acetaminophen-induced acute liver failure (AALF) involves innate immunity, but the role of hepatic macrophages (h-mφ) is debated.
- Understanding h-mφ function in human AALF is crucial for determining their impact on liver injury and repair.
Purpose of the Study:
- To investigate the role of chemokine ligand 2 (CCL2) in monocyte recruitment to the liver in AALF.
- To determine if h-mφ contribute to inflammation or tissue repair in human AALF.
Main Methods:
- Evaluated circulating monocytes, their CCR2 expression, and serum CCL2 in AALF patients.
- Quantified h-mφ subsets (circulation-derived and resident) and proliferation markers (Ki67) in liver biopsies using immunohistochemistry.
- Measured inflammatory cytokine levels in liver tissue via proteome array.
Main Results:
- AALF patients showed depleted circulating monocytes, with lower levels in those with adverse outcomes.
- Elevated serum and hepatic CCL2 levels correlated with CCR2 expression on monocytes, indicating CCL2-dependent recruitment.
- Increased MAC387+ and CD68+/Ki67+ h-mφ were observed in AALF livers, alongside elevated inflammatory cytokines (CCL2, CCL3, IL-6, IL-10, TGF-β1).
Conclusions:
- Hepatic macrophages in AALF expand through resident cell proliferation and CCL2-driven monocyte recruitment.
- The presence of h-mφ within an anti-inflammatory/regenerative microenvironment suggests their involvement in resolving inflammation and promoting tissue repair in AALF.
