Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice

• Published in: The American journal of pathology Vol. 174; no. 5; pp. 1766 - 1775
• Main Authors: Mitchell, Claudia, Couton, Dominique, Couty, Jean-Pierre, Anson, Marie, Crain, Anne-Marie, Bizet, Vinciane, Rénia, Laurent, Pol, Stanislas, Mallet, Vincent, Gilgenkrantz, Hélène
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-05-2009; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Carbon Tetrachloride - toxicity; CD11b Antigen - metabolism; CD11c Antigen - metabolism; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; Immunoenzyme Techniques; Investigative techniques, diagnostic techniques (general aspects); Liver - drug effects; Liver - injuries; Liver - metabolism; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Other diseases. Semiology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Receptors, CCR2 - physiology; Regular; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Hepatic fibrosis; Vertebrata; Anatomic pathology; Mammalia; Mouse; Animal; Rodentia; CCR2 chemokine receptor; Digestive diseases; Hepatic disease; Chemokine receptor; CC chemokine
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080632

Inflammation has been shown to induce the progression of fibrosis in response to liver injury. Among inflammatory cells, macrophages and lymphocytes play major roles in both the constitution and resolution of liver fibrosis. The chemokine receptor CCR2 is involved in the recruitment of monocytes to injury sites, and it is known to be induced during the progression of fibrosis in humans. However, its specific role during this process has not yet been unveiled. We first demonstrated that, compared with wild-type mice, CCR2 knockout animals presented a delay in liver injury after acute CCl4 injection, accompanied by a reduction in infiltrating macrophage populations. We then induced fibrosis using repeated injections of CCl4 and observed a significantly lower level of fibrotic scars at the peak of fibrosis in mutant animals compared with control mice. This diminished fibrosis was associated with a reduction in F4/80+ CD11b+ and CD11c+ populations at the sites of injury. Subsequent analysis of the kinetics of the resolution of fibrosis showed that fibrosis rapidly regressed in wild-type, but not in CCR2−/− mice. The persistence of hepatic injury in mutant animals was correlated with sustained tissue inhibitor of metalloproteinase-1 mRNA expression levels and a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-13 expression levels. In conclusion, these findings underline the role of the CCR2 signaling pathway in both the constitution and resolution of liver fibrotic scars.