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

P Ramachandran, A Pellicoro… - Proceedings of the …, 2012 - National Acad Sciences
P Ramachandran, A Pellicoro, MA Vernon, L Boulter, RL Aucott, A Ali, SN Hartland…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
Although macrophages are widely recognized to have a profibrotic role in inflammation, we
have used a highly tractable CCl4-induced model of reversible hepatic fibrosis to identify
and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto
elusive restorative macrophage. This CD11Bhi F4/80int Ly-6Clo 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 …
Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl4-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11Bhi F4/80int Ly-6Clo 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-6Chi monocytes, a common origin with profibrotic Ly-6Chi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6Clo subset, compared with Ly-6Chi 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.
National Acad Sciences