Abstract
Macrophages have been found to both promote liver fibrosis and contribute to its resolution by acquiring different phenotypes based on signals from the micro-environment. The best-characterized phenotypes in the macrophage spectrum are labeled M1 (classically activated) and M2 (alternatively activated). Until now the in situ localization of these phenotypes in diseased livers is poorly described. In this study, we therefore aimed to localize and quantify M1- and M2-dominant macrophages in diseased mouse and human livers. The scarred collagen-rich areas in cirrhotic human livers and in CCl4-damaged mouse livers contained many macrophages. Though total numbers of macrophages were higher in fibrotic livers, the number of parenchymal CD68-positive macrophages was significantly lower as compared to normal. Scar-associated macrophages were further characterized as either M1-dominant (IRF-5 and interleukin-12) or M2-dominant (CD206, transglutaminase-2, and YM-1) and significantly higher numbers of both of these were detected in diseased livers as compared to healthy human and mouse livers. Interestingly, in mouse, livers undergoing resolution of fibrosis, the total number of CD68+ macrophages was significantly lower compared to their fibrotic counterparts. M2-dominant (YM-1) macrophages were almost completely gone in livers undergoing resolution, while numbers of M1-dominant (IRF-5) macrophages were almost unchanged and the proteolytic activity (MMP9) increased. In conclusion, this study shows the distribution of macrophage subsets in livers of both human and murine origin. The presence of M1- and M2-dominant macrophages side by side in fibrotic lesions suggests that both are involved in fibrotic responses, while the persistence of M1-dominant macrophages during resolution may indicate their importance in regression of fibrosis. This study emphasizes that immunohistochemical detection of M1/M2-dominant macrophages provides valuable information in addition to widely used flow cytometry and gene analysis.
Highlights
Chronic injury of the liver leads to induction of fibrogenic processes that can progress to cirrhosis, a state in which excessive extracellular matrix deposition hampers normal liver functions
As compared to normal livers, a higher number of CD68-positive cells was found in fibrotic livers, and these macrophages predominantly concentrated in scars during advanced fibrosis (Figures 1C,D,G)
The fact that we find similar distributions of macrophage phenotypes in end-stage disease of a number of different etiologies may point at converging disease mechanisms irrespective of cause
Summary
Chronic injury of the liver leads to induction of fibrogenic processes that can progress to cirrhosis, a state in which excessive extracellular matrix deposition hampers normal liver functions. Kupffer cells are well-known producers of reactive oxygen species, cytokines and chemokines, that perpetuate hepatic inflammatory responses, and of matrix-degrading enzymes. These macrophages can phagocytose micro-organisms, apoptotic cells, and cellular debris generated during tissue injury and remodeling. Duffield et al [8] clearly showed that Kupffer cells exert different, even opposing roles during various stages of liver fibrosis They showed that macrophage activities during the injury phase were predominantly associated with promotion of matrix deposition and HSC activities, while during recovery macrophages were associated with enhanced resolution and higher production of matrix metalloproteinases (MMPs) [8, 9]. These diverse roles may indicate that activated macrophages differentiate into diverse phenotypes during various stages of liver disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
