Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice.
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 CCl(4) injection, accompanied by a reduction in infiltrating macrophage populations. We then induced fibrosis using repeated injections of CCl(4) 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.
Institut Cochin, Université Paris Descartes, Centre National de Researche Scientifique (UMR 8104), Paris, France.
Claudia
C
Mitchell
Dominique
D
Couton
Jean-Pierre
JP
Couty
Marie
M
Anson
Anne-Marie
AM
Crain
Vinciane
V
Bizet
Laurent
L
Rénia
Stanislas
S
Pol
Vincent
V
Mallet
Hélène
H
Gilgenkrantz
D000818:Animals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D039481:CD11b Antigen; D039521:CD11c Antigen; C515335:Ccr2 protein, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019715:Tissue Inhibitor of Metalloproteinase-1; D002251:Carbon Tetrachloride; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2