Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl(4)-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macroph...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 109; číslo 46; s. E3186
Hlavní autoři:	Ramachandran, Prakash, Pellicoro, Antonella, Vernon, Madeleine A, Boulter, Luke, Aucott, Rebecca L, Ali, Aysha, Hartland, Stephen N, Snowdon, Victoria K, Cappon, Andrea, Gordon-Walker, Timothy T, Williams, Mike J, Dunbar, Donald R, Manning, Jonathan R, van Rooijen, Nico, Fallowfield, Jonathan A, Forbes, Stuart J, Iredale, John P
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 13.11.2012
Témata:	Animals Antigens, Ly - genetics Antigens, Ly - immunology Carbon Tetrachloride - toxicity Carbon Tetrachloride Poisoning - genetics Carbon Tetrachloride Poisoning - immunology Carbon Tetrachloride Poisoning - pathology CD11b Antigen - genetics CD11b Antigen - immunology Gene Expression Regulation - drug effects Gene Expression Regulation - genetics Gene Expression Regulation - immunology Insulin-Like Growth Factor I - genetics Insulin-Like Growth Factor I - immunology Liver Cirrhosis - chemically induced Liver Cirrhosis - genetics Liver Cirrhosis - immunology Liver Cirrhosis - pathology Macrophages - immunology Macrophages - pathology MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - genetics MAP Kinase Signaling System - immunology Matrix Metalloproteinase 12 - genetics Matrix Metalloproteinase 12 - immunology Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - immunology Mice Mice, Transgenic Monocytes - immunology Monocytes - pathology
ISSN:	1091-6490, 1091-6490
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Shrnutí:	Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl(4)-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B(hi) F4/80(int) Ly-6C(lo) macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C(hi) monocytes, a common origin with profibrotic Ly-6C(hi) macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C(lo) subset, compared with Ly-6C(hi) macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1119964109