期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 46, 页码 E3186-E3195出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1119964109
关键词
Kupffer Cell; collagen; degradation; myofibroblast; proliferation
资金
- Wellcome Trust Research Training Fellowships
- Medical Research Council Programme grant
- Medical Research Council PhD studentship
- Royal College of Surgeons of Edinburgh
- Medical Research Council Research Training Fellowships
- Edinburgh British Heart Foundation Centre of Research Excellence
- Academy of Medical Sciences
- Health Foundation
- Sir Jules Thorn Trust
- Academy of Medical Sciences (AMS) [AMS-CSF3-Fallowfield] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20310000] Funding Source: researchfish
- Medical Research Council [G1000868, G0900446, G0901697, G0700582, G84/6205, MR/K001744/1, G0600033, G0700711B] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [07JTA] Funding Source: researchfish
- BBSRC [BBS/E/D/20310000] Funding Source: UKRI
- MRC [G1000868, G0901697, G0900446, G0600033, MR/K001744/1, G84/6205, G0700582] Funding Source: UKRI
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 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.
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