Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.

Macrophages perform both injury-inducing and repair-promoting tasks in different models of inflammation, leading to a model of macrophage function in which distinct patterns of activation have been proposed. We investigated macrophage function mechanistically in a reversible model of liver injury in which the injury and recovery phases are distinct. Carbon tetrachloride---induced liver fibrosis revealed scar-associated macrophages that persisted throughout recovery. A transgenic mouse (CD11b-DTR) was generated in which macrophages could be selectively depleted. Macrophage depletion when liver fibrosis was advanced resulted in reduced scarring and fewer myofibroblasts. Macrophage depletion during recovery, by contrast, led to a failure of matrix degradation. These data provide the first clear evidence that functionally distinct subpopulations of macrophages exist in the same tissue and that these macrophages play critical roles in both the injury and recovery phases of inflammatory scarring.

[1]  R. Brentani,et al.  Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections , 1979, The Histochemical Journal.

[2]  J. Fallowfield,et al.  Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. , 2004, Gastroenterology.

[3]  M. Rugge,et al.  A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. , 2004, Gastroenterology.

[4]  A. Desmoulière,et al.  Normal and Pathologic Soft Tissue Remodeling: Role of the Myofibroblast, with Special Emphasis on Liver and Kidney Fibrosis , 2003, Laboratory Investigation.

[5]  S. Gordon,et al.  Dectin-1 Expression and Function Are Enhanced on Alternatively Activated and GM-CSF-Treated Macrophages and Are Negatively Regulated by IL-10, Dexamethasone, and Lipopolysaccharide 1 , 2003, The Journal of Immunology.

[6]  R. Atkins,et al.  Macrophages act as effectors of tissue damage in acute renal allograft rejection , 2003, Transplantation.

[7]  S. Krane,et al.  Mutation in collagen‐I that confers resistance to the action of collagenase results in failure of recovery from CCl4‐induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  J. Duffield.  The inflammatory macrophage , 2003 .

[9]  J. Duffield.  The inflammatory macrophage: a story of Jekyll and Hyde. , 2003, Clinical science.

[10]  K. Kivirikko,et al.  Inactivation of the Lysyl Oxidase Gene Lox Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice , 2002, Circulation.

[11]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[12]  P. De Baetselier,et al.  FIZZ1 and Ym as Tools to Discriminate between Differentially Activated Macrophages , 2002, Developmental immunology.

[13]  Steffen Jung,et al.  In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. , 2002, Immunity.

[14]  I. Fishbein,et al.  Macrophage Depletion by Clodronate-Containing Liposomes Reduces Neointimal Formation After Balloon Injury in Rats and Rabbits , 2002, Circulation.

[15]  John P. Iredale,et al.  Inhibition of Apoptosis of Activated Hepatic Stellate Cells by Tissue Inhibitor of Metalloproteinase-1 Is Mediated via Effects on Matrix Metalloproteinase Inhibition , 2002, The Journal of Biological Chemistry.

[16]  J. Lamb,et al.  Inhibitory Effects of Apoptotic Cell Ingestion upon Endotoxin-Driven Myeloid Dendritic Cell Maturation1 , 2002, The Journal of Immunology.

[17]  J. Floege,et al.  Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis. , 2001, Journal of the American Society of Nephrology : JASN.

[18]  B. Ryffel,et al.  Suppression by apoptotic cells defines tumor necrosis factor-mediated induction of glomerular mesangial cell apoptosis by activated macrophages. , 2001, The American journal of pathology.

[19]  H. Yonekawa,et al.  Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice , 2001, Nature Biotechnology.

[20]  J. Iredale.  Hepatic Stellate Cell Behavior during Resolution of Liver Injury , 2001, Seminars in liver disease.

[21]  N. Van Rooijen,et al.  A critical role for alveolar macrophages in elicitation of pulmonary immune fibrosis , 2000, Immunology.

[22]  B. Antus,et al.  Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. , 2000, Cellular immunology.

[23]  T. Langmann,et al.  Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro‐ and antiinflammatory stimuli , 2000, Journal of leukocyte biology.

[24]  M. Daha,et al.  Distinctive roles of neutrophils and monocytes in anti-thy-1 nephritis. , 2000, The American journal of pathology.

[25]  V. Fadok,et al.  Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-beta in macrophages that have ingested apoptotic cells. , 1999, Journal of immunology.

[26]  C. Alpers,et al.  Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. , 1999, Kidney international.

[27]  K. Lehti,et al.  MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells , 1999, Hepatology.

[28]  J. Hughes,et al.  Role of Fas (CD95) in tubulointerstitial disease induced by unilateral ureteric obstruction. , 1999, AJP - Renal Physiology.

[29]  R. Lang,et al.  Macrophages kill capillary cells in G1 phase of the cell cycle during programmed vascular regression. , 1999, Development.

[30]  S. Goerdt,et al.  Other functions, other genes: alternative activation of antigen-presenting cells. , 1999, Immunity.

[31]  L. Wahl,et al.  Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms. , 1998, Journal of immunology.

[32]  A. Rees,et al.  Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines. , 1998, Journal of immunology.

[33]  J. Iredale,et al.  Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. , 1998, The Journal of clinical investigation.

[34]  M. Solioz,et al.  False positive staining in the TUNEL assay to detect apoptosis in liver and intestine is caused by endogenous nucleases and inhibited by diethyl pyrocarbonate. , 1998, Molecular pathology : MP.

[35]  T. Mariani,et al.  Collagenase-3 induction in rat lung fibroblasts requires the combined effects of tumor necrosis factor-alpha and 12-lipoxygenase metabolites: a model of macrophage-induced, fibroblast-driven extracellular matrix remodeling during inflammatory lung injury. , 1998, Molecular biology of the cell.

[36]  V. Fadok,et al.  Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. , 1998, The Journal of clinical investigation.

[37]  S. Goerdt,et al.  Differences in angiogenic potential of classically vs alternatively activated macrophages. , 1997, Immunobiology.

[38]  R. Lang,et al.  Macrophages induce apoptosis in normal cells in vivo. , 1997, Development.

[39]  J. Schalkwijk,et al.  Decreased PMN accumulation and glomerular damage by clodronate liposome treatment in PMN-dependent anti-GBM nephritis in mice. , 1997, Experimental nephrology.

[40]  N. Van Rooijen,et al.  Kupffer cell depletion by liposome‐delivered drugs: Comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid , 1996, Hepatology.

[41]  R. Pierce,et al.  Monocytic cell type-specific transcriptional induction of collagenase. , 1996, The Journal of clinical investigation.

[42]  R. Perlmutter,et al.  The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice. , 1995, Blood.

[43]  J. Hughes,et al.  Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. , 1994, The Journal of clinical investigation.

[44]  D. Russell,et al.  Expression cloning of a diphtheria toxin receptor: Identity with a heparin-binding EGF-like growth factor precursor , 1992, Cell.

[45]  S. Gordon,et al.  Macrophages in haemopoietic and other tissues of the developing mouse detected by the monoclonal antibody F4/80. , 1991, Development.

[46]  T. Roderick,et al.  FVB/N: an inbred mouse strain preferable for transgenic analyses. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[47]  V. Cattell,et al.  Glomeruli synthesize nitrite in active Heymann nephritis; the source is infiltrating macrophages. , 1991, Kidney international.

[48]  M. Sporn,et al.  Deactivation of macrophages by transforming growth factor-β , 1988, Nature.

[49]  M. Sporn,et al.  Deactivation of macrophages by transforming growth factor-beta. , 1988, Nature.

[50]  R. Ross,et al.  The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. , 1975, The American journal of pathology.