Title | Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT, Williams MJ, Dunbar DR, Manning JR, van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP |
Journal | Proc Natl Acad Sci U S A |
Volume | 109 |
Issue | 46 |
Pagination | E3186-95 |
Date Published | 2012 Nov 13 |
ISSN | 1091-6490 |
Keywords | Animals, Antigens, CD11b, Antigens, Ly, Carbon Tetrachloride, Carbon Tetrachloride Poisoning, Gene Expression Regulation, Insulin-Like Growth Factor I, Liver Cirrhosis, Macrophages, MAP Kinase Signaling System, Matrix Metalloproteinase 12, Matrix Metalloproteinase 9, Mice, Mice, Transgenic, Monocytes |
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. |
DOI | 10.1073/pnas.1119964109 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 23100531 |
PubMed Central ID | PMC3503234 |
Grant List | G0600033 / / Medical Research Council / United Kingdom G0700582 / / Medical Research Council / United Kingdom G0900446 / / Medical Research Council / United Kingdom G0901697 / / Medical Research Council / United Kingdom G1000868 / / Medical Research Council / United Kingdom G84/6205 / / Medical Research Council / United Kingdom MR/K001744/1 / / Medical Research Council / United Kingdom / / Medical Research Council / United Kingdom / / Wellcome Trust / United Kingdom |