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Published on: November 27, 2019
Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury
Michael P Holt1, LinLing Cheng, Cynthia Ju
1Department of Pharmaceutical Sciences, University of Colorado Denver, 4200 East 9th Avenue, Denver, CO 80262, USA.
Abstract:
The role of macrophages in the pathogenesis of acetaminophen (APAP)-induced liver injury remains controversial, as it has been demonstrated that these cells display pro-toxicant and hepato-protective functions. This controversy may stem from the heterogeneity and/or plasticity of macrophages and the difficulty in distinguishing and differentially studying subpopulations of macrophages in the liver. In the present study, using flow cytometric analysis and fluorescence-labeled antibodies against specific cell surface macrophage markers, we were able to, for the first time, identify an APAP-induced macrophage (IM) population distinct from resident Kupffer cells. The data demonstrated that the IMs were derived from circulating monocytes that infiltrated the liver following APAP-induced liver injury. The IMs exhibited a phenotype consistent with that of alternatively activated macrophages and demonstrated the ability to phagocytize apoptotic cells and induce apoptosis of neutrophils. Furthermore, in the absence of the IMs, the resolution of hepatic damage following APAP-induced hepatotoxicity was delayed in CCR2(-/-) mice compared with wild-type mice. These findings likely contribute to the role of the IMs in the processes of tissue repair, including counteracting inflammation and promoting angiogenesis. The present study also demonstrated the ability of separating populations of macrophages and delineating distinct functions of each group in future studies of inflammatory disease in the liver and other tissues.
Insights
Acetaminophen (APAP) induces distinct liver macrophages (IMs) from circulating monocytes. These IMs aid liver repair by clearing debris and promoting healing, resolving APAP-induced liver injury.
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- Macrophages play complex roles in acetaminophen (APAP)-induced liver injury, exhibiting both harmful and protective functions.
- Macrophage heterogeneity and plasticity complicate understanding their specific roles in liver pathogenesis.
- Distinguishing macrophage subpopulations in the liver during injury is challenging.
Purpose of the Study:
- To identify and characterize distinct macrophage populations involved in APAP-induced liver injury.
- To investigate the origin and function of APAP-induced macrophages (IMs).
- To elucidate the role of IMs in the resolution of liver damage.
Main Methods:
- Flow cytometry and fluorescence-labeled antibodies were used to identify macrophage subsets.
- Analysis of macrophage populations in wild-type and CCR2(-/-) mice following APAP administration.
- Assessment of macrophage phagocytic activity and impact on neutrophil apoptosis.
Main Results:
- An APAP-induced macrophage (IM) population, distinct from Kupffer cells, was identified.
- IMs originate from circulating monocytes infiltrating the liver during APAP injury.
- IMs display an alternatively activated phenotype, phagocytose apoptotic cells, and induce neutrophil apoptosis.
- Absence of IMs (in CCR2(-/-) mice) delayed liver damage resolution.
Conclusions:
- IMs play a crucial role in resolving APAP-induced liver injury through tissue repair mechanisms.
- These macrophages contribute to counteracting inflammation and promoting angiogenesis.
- The study highlights the potential for dissecting distinct macrophage functions in liver inflammation and other diseases.
