title: Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis.
abstract: 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.
authors.affiliation: University of Edinburgh/Medical Research Council Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Prakash
authors.initials: P
authors.lastname: Ramachandran
authors.forename: Antonella
authors.initials: A
authors.lastname: Pellicoro
authors.forename: Madeleine A
authors.initials: MA
authors.lastname: Vernon
authors.forename: Luke
authors.initials: L
authors.lastname: Boulter
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Aucott
authors.forename: Aysha
authors.initials: A
authors.lastname: Ali
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Hartland
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Snowdon
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappon
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Gordon-Walker
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Williams
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Manning
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fallowfield
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology*; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000276:immunology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C494192:Ly-6C antigen, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053508:Matrix Metalloproteinase 12