Download PDF
Semin Liver Dis 2010; 30(3): 245-257
DOI: 10.1055/s-0030-1255354
© Thieme Medical Publishers

Macrophages: Master Regulators of Inflammation and Fibrosis

Thomas A. Wynn1 , Luke Barron1
  • 1Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Further Information

Publication History

Publication Date:
21 July 2010 (online)

    Permissions and Reprints

ABSTRACT

Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-β1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master “producers” of fibrosis, this review will illustrate how macrophages function as the master “regulators” of fibrosis.

KEYWORDS

Fibrosis - inflammation - collagen - wound healing - stellate cell - myofibroblasts - interleukin-13 - transforming growth factor beta - tumor necrosis factor - interleukin-1 - interleukin-17 - arginase - Relm-alpha - chitinase

REFERENCES

  • 1 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115 209-218
    CrossrefPubMedGoogle Scholar
  • 2 Iredale J P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ.  J Clin Invest. 2007;  117 539-548
    CrossrefPubMedGoogle Scholar
  • 3 Friedman S L. Mechanisms of hepatic fibrogenesis.  Gastroenterology. 2008;  134 1655-1669
    CrossrefPubMedGoogle Scholar
  • 4 Friedman S L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.  Physiol Rev. 2008;  88 125-172
    CrossrefPubMedGoogle Scholar
  • 5 Wallace K, Burt A D, Wright M C. Liver fibrosis.  Biochem J. 2008;  411 1-18
    CrossrefPubMedGoogle Scholar
  • 6 Luckey S W, Petersen D R. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats.  Exp Mol Pathol. 2001;  71 226-240
    CrossrefPubMedGoogle Scholar
  • 7 Ramadori G, Armbrust T. Cytokines in the liver.  Eur J Gastroenterol Hepatol. 2001;  13 777-784
    CrossrefPubMedGoogle Scholar
  • 8 Ramm G A, Nair V G, Bridle K R, Shepherd R W, Crawford D H. Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia.  Am J Pathol. 1998;  153 527-535
    CrossrefPubMedGoogle Scholar
  • 9 Leicester K L, Olynyk J K, Brunt E M, Britton R S, Bacon B R. CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis.  Liver Int. 2004;  24 446-451
    CrossrefPubMedGoogle Scholar
  • 10 Thompson R W, Pesce J T, Ramalingam T et al.. Cationic amino acid transporter-2 regulates immunity by modulating arginase activity.  PLoS Pathog. 2008;  4 e1000023
    CrossrefPubMedGoogle Scholar
  • 11 Friedman S L, Arthur M J. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors.  J Clin Invest. 1989;  84 1780-1785
    CrossrefPubMedGoogle Scholar
  • 12 Wahl S M, McCartney-Francis N, Allen J B, Dougherty E B, Dougherty S F. Macrophage production of TGF-beta and regulation by TGF-beta.  Ann N Y Acad Sci. 1990;  593 188-196
    CrossrefPubMedGoogle Scholar
  • 13 Bonner J C, Osornio-Vargas A R, Badgett A, Brody A R. Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages.  Am J Respir Cell Mol Biol. 1991;  5 539-547
    PubMedGoogle Scholar
  • 14 Wynn T A. Cellular and molecular mechanisms of fibrosis.  J Pathol. 2008;  214 199-210
    CrossrefPubMedGoogle Scholar
  • 15 Gasse P, Mary C, Guenon I et al.. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.  J Clin Invest. 2007;  117 3786-3799
    PubMedGoogle Scholar
  • 16 Kaviratne M, Hesse M, Leusink M et al.. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent.  J Immunol. 2004;  173 4020-4029
    PubMedGoogle Scholar
  • 17 Olman M A. Beyond TGF-beta: a prostaglandin promotes fibrosis.  Nat Med. 2009;  15 1360-1361
    CrossrefPubMedGoogle Scholar
  • 18 Oga T, Matsuoka T, Yao C et al.. Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.  Nat Med. 2009;  15 1426-1430
    CrossrefPubMedGoogle Scholar
  • 19 Duffield J S, Forbes S J, Constandinou C M et al.. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.  J Clin Invest. 2005;  115 56-65
    CrossrefPubMedGoogle Scholar
  • 20 Hotchkiss R S, Strasser A, McDunn J E, Swanson P E. Cell death.  N Engl J Med. 2009;  361 1570-1583
    CrossrefPubMedGoogle Scholar
  • 21 Rock K L, Kono H. The inflammatory response to cell death.  Annu Rev Pathol. 2008;  3 99-126
    CrossrefPubMedGoogle Scholar
  • 22 Fadok V A, Bratton D L, Konowal A, Freed P W, Westcott J Y, Henson P M. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.  J Clin Invest. 1998;  101 890-898
    CrossrefPubMedGoogle Scholar
  • 23 Takehara T, Tatsumi T, Suzuki T et al.. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses.  Gastroenterology. 2004;  127 1189-1197
    CrossrefPubMedGoogle Scholar
  • 24 Iredale J P, Benyon R C, Pickering J et al.. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.  J Clin Invest. 1998;  102 538-549
    CrossrefPubMedGoogle Scholar
  • 25 Wynn T A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.  J Clin Invest. 2007;  117 524-529
    CrossrefPubMedGoogle Scholar
  • 26 Otogawa K, Kinoshita K, Fujii H et al.. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis.  Am J Pathol. 2007;  170 967-980
    CrossrefPubMedGoogle Scholar
  • 27 Shi J, Aisaki K, Ikawa Y, Wake K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride.  Am J Pathol. 1998;  153 515-525
    CrossrefPubMedGoogle Scholar
  • 28 Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman S L, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression.  Gastroenterology. 2008;  135 660-670
    CrossrefPubMedGoogle Scholar
  • 29 Douglass A, Wallace K, Parr R et al.. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury.  J Hepatol. 2008;  49 88-98
    CrossrefPubMedGoogle Scholar
  • 30 Atabai K, Jame S, Azhar N et al.. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages.  J Clin Invest. 2009;  119 3713-3722
    CrossrefPubMedGoogle Scholar
  • 31 Sanderson N, Factor V, Nagy P et al.. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.  Proc Natl Acad Sci U S A. 1995;  92 2572-2576
    CrossrefPubMedGoogle Scholar
  • 32 Bissell D M, Wang S S, Jarnagin W R, Roll F J. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.  J Clin Invest. 1995;  96 447-455
    CrossrefPubMedGoogle Scholar
  • 33 Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases.  J Pathol. 2003;  200 500-503
    CrossrefPubMedGoogle Scholar
  • 34 Karlmark K R, Weiskirchen R, Zimmermann H W et al.. Hepatic recruitment of the inflammatory Gr1 + monocyte subset upon liver injury promotes hepatic fibrosis.  Hepatology. 2009;  50 261-274
    CrossrefPubMedGoogle Scholar
  • 35 Lin S L, Castaño A P, Nowlin B T, Lupher Jr M L, Duffield J S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations.  J Immunol. 2009;  183 6733-6743
    CrossrefPubMedGoogle Scholar
  • 36 Gressner A M, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis.  Front Biosci. 2002;  7 d793-d807
    CrossrefPubMedGoogle Scholar
  • 37 Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis.  J Exp Med. 2003;  198 1179-1188
    CrossrefPubMedGoogle Scholar
  • 38 Schmid-Kotsas A, Gross H J, Menke A et al.. Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-fibronectin in cultured pancreatic stellate cells.  Am J Pathol. 1999;  155 1749-1758
    CrossrefPubMedGoogle Scholar
  • 39 Cameron R G, Blendis L M, Neuman M G. Accumulation of macrophages in primary sclerosing cholangitis.  Clin Biochem. 2001;  34 195-201
    CrossrefPubMedGoogle Scholar
  • 40 Xing Z, Tremblay G M, Sime P J, Gauldie J. Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation.  Am J Pathol. 1997;  150 59-66
    PubMedGoogle Scholar
  • 41 Lee C G, Homer R J, Zhu Z et al.. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).  J Exp Med. 2001;  194 809-821
    CrossrefPubMedGoogle Scholar
  • 42 Fattouh R, Jordana M. TGF-beta, eosinophils and IL-13 in allergic airway remodeling: a critical appraisal with therapeutic considerations.  Inflamm Allergy Drug Targets. 2008;  7 224-236
    CrossrefPubMedGoogle Scholar
  • 43 Fattouh R, Midence N G, Arias K et al.. Transforming growth factor-beta regulates house dust mite-induced allergic airway inflammation but not airway remodeling.  Am J Respir Crit Care Med. 2008;  177 593-603
    CrossrefPubMedGoogle Scholar
  • 44 Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J. Effects of gadolinium chloride (GdCl(3)) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions.  J Comp Pathol. 2005;  133 92-102
    CrossrefPubMedGoogle Scholar
  • 45 Taylor P R, Martinez-Pomares L, Stacey M, Lin H H, Brown G D, Gordon S. Macrophage receptors and immune recognition.  Annu Rev Immunol. 2005;  23 901-944
    CrossrefPubMedGoogle Scholar
  • 46 Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation.  Semin Liver Dis. 2007;  27 339-350
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Meneghin A, Hogaboam C M. Infectious disease, the innate immune response, and fibrosis.  J Clin Invest. 2007;  117 530-538
    CrossrefPubMedGoogle Scholar
  • 48 Seki E, De Minicis S, Osterreicher C H et al.. TLR4 enhances TGF-beta signaling and hepatic fibrosis.  Nat Med. 2007;  13 1324-1332
    CrossrefPubMedGoogle Scholar
  • 49 Marra F, DeFranco R, Grappone C et al.. Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E.  J Investig Med. 1999;  47 66-75
    PubMedGoogle Scholar
  • 50 Tsuneyama K, Harada K, Yasoshima M et al.. Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis.  J Pathol. 2001;  193 102-109
    CrossrefPubMedGoogle Scholar
  • 51 Seki E, de Minicis S, Inokuchi S et al.. CCR2 promotes hepatic fibrosis in mice.  Hepatology. 2009;  50 185-197
    CrossrefPubMedGoogle Scholar
  • 52 Okuma T, Terasaki Y, Kaikita K et al.. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.  J Pathol. 2004;  204 594-604
    CrossrefPubMedGoogle Scholar
  • 53 Seki E, De Minicis S, Gwak G Y et al.. CCR1 and CCR5 promote hepatic fibrosis in mice.  J Clin Invest. 2009;  119 1858-1870
    PubMedGoogle Scholar
  • 54 Keane M P, Belperio J A, Moore T A et al.. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.  J Immunol. 1999;  162 5511-5518
    PubMedGoogle Scholar
  • 55 Kohan M, Bader R, Puxeddu I, Levi-Schaffer F, Breuer R, Berkman N. Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling.  Clin Exp Allergy. 2007;  37 1444-1454
    PubMedGoogle Scholar
  • 56 Berman J S, Serlin D, Li X et al.. Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice.  Am J Physiol Lung Cell Mol Physiol. 2004;  286 L1311-L1318
    CrossrefPubMedGoogle Scholar
  • 57 Kawashima R, Mochida S, Matsui A et al.. Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas.  Biochem Biophys Res Commun. 1999;  256 527-531
    CrossrefPubMedGoogle Scholar
  • 58 Persy V P, Verhulst A, Ysebaert D K, De Greef K E, De Broe M E. Reduced postischemic macrophage infiltration and interstitial fibrosis in osteopontin knockout mice.  Kidney Int. 2003;  63 543-553
    CrossrefPubMedGoogle Scholar
  • 59 Sahai A, Malladi P, Melin-Aldana H, Green R M, Whitington P F. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model.  Am J Physiol Gastrointest Liver Physiol. 2004;  287 G264-G273
    CrossrefPubMedGoogle Scholar
  • 60 Lorena D, Darby I A, Gadeau A P et al.. Osteopontin expression in normal and fibrotic liver. altered liver healing in osteopontin-deficient mice.  J Hepatol. 2006;  44 383-390
    CrossrefPubMedGoogle Scholar
  • 61 Wang Y, Mochida S, Kawashima R et al.. Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver.  J Gastroenterol. 2000;  35 696-701
    CrossrefPubMedGoogle Scholar
  • 62 Martinet Y, Rom W N, Grotendorst G R, Martin G R, Crystal R G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis.  N Engl J Med. 1987;  317 202-209
    CrossrefPubMedGoogle Scholar
  • 63 Bonner J C. Regulation of PDGF and its receptors in fibrotic diseases.  Cytokine Growth Factor Rev. 2004;  15 255-273
    CrossrefPubMedGoogle Scholar
  • 64 Yoshiji H, Noguchi R, Kuriyama S et al.. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats.  Am J Physiol Gastrointest Liver Physiol. 2005;  288 G907-G913
    CrossrefPubMedGoogle Scholar
  • 65 Zhang Y, Lee T C, Guillemin B, Yu M C, Rom W N. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure.  J Immunol. 1993;  150 4188-4196
    PubMedGoogle Scholar
  • 66 Kolb M, Margetts P J, Anthony D C, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis.  J Clin Invest. 2001;  107 1529-1536
    CrossrefPubMedGoogle Scholar
  • 67 Wilson M S, Madala S K, Ramalingam T R et al.. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent.  J Exp Med. 2010;  207 535-552
    CrossrefPubMedGoogle Scholar
  • 68 Tiggelman A M, Boers W, Linthorst C, Sala M, Chamuleau R A. Collagen synthesis by human liver (myo)fibroblasts in culture: evidence for a regulatory role of IL-1 beta, IL-4, TGF beta and IFN gamma.  J Hepatol. 1995;  23 307-317
    CrossrefPubMedGoogle Scholar
  • 69 Mancini R, Benedetti A, Jezequel A M. An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver.  Virchows Arch. 1994;  424 25-31
    PubMedGoogle Scholar
  • 70 Leyland H, Gentry J, Arthur M J, Benyon R C. The plasminogen-activating system in hepatic stellate cells.  Hepatology. 1996;  24 1172-1178
    CrossrefPubMedGoogle Scholar
  • 71 Salgado S, Garcia J, Vera J et al.. Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy.  Mol Ther. 2000;  2 545-551
    CrossrefPubMedGoogle Scholar
  • 72 Henderson N C, Mackinnon A C, Farnworth S L et al.. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis.  Am J Pathol. 2008;  172 288-298
    CrossrefPubMedGoogle Scholar
  • 73 Wynes M W, Riches D W. Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13.  J Immunol. 2003;  171 3550-3559
    PubMedGoogle Scholar
  • 74 Büttner C, Skupin A, Reimann T et al.. Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4.  Am J Respir Cell Mol Biol. 1997;  17 315-325
    PubMedGoogle Scholar
  • 75 Hayashi N, Matsui K, Tsutsui H et al.. Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2 differentiation of hepatic T cells in response to worm antigens.  J Immunol. 1999;  163 6702-6711
    PubMedGoogle Scholar
  • 76 Wynn T A. Fibrotic disease and the T(H)1/T(H)2 paradigm.  Nat Rev Immunol. 2004;  4 583-594
    CrossrefPubMedGoogle Scholar
  • 77 Chiaramonte M G, Donaldson D D, Cheever A W, Wynn T A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.  J Clin Invest. 1999;  104 777-785
    CrossrefPubMedGoogle Scholar
  • 78 Oriente A, Fedarko N S, Pacocha S E, Huang S K, Lichtenstein L M, Essayan D M. Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts.  J Pharmacol Exp Ther. 2000;  292 988-994
    PubMedGoogle Scholar
  • 79 Murray L A, Argentieri R L, Farrell F X et al.. Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2.  Int J Biochem Cell Biol. 2008;  40 2174-2182
    CrossrefPubMedGoogle Scholar
  • 80 Hashimoto S, Gon Y, Takeshita I, Maruoka S, Horie T. IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway.  J Allergy Clin Immunol. 2001;  107 1001-1008
    CrossrefPubMedGoogle Scholar
  • 81 Wynn T A, Cheever A W, Jankovic D et al.. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection.  Nature. 1995;  376 594-596
    CrossrefPubMedGoogle Scholar
  • 82 Shi Z, Wakil A E, Rockey D C. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses.  Proc Natl Acad Sci U S A. 1997;  94 10663-10668
    CrossrefPubMedGoogle Scholar
  • 83 Chiaramonte M G, Cheever A W, Malley J D, Donaldson D D, Wynn T A. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis.  Hepatology. 2001;  34 273-282
    CrossrefPubMedGoogle Scholar
  • 84 Hoffmann K F, Cheever A W, Wynn T A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.  J Immunol. 2000;  164 6406-6416
    PubMedGoogle Scholar
  • 85 Pesce J, Kaviratne M, Ramalingam T R et al.. The IL-21 receptor augments Th2 effector function and alternative macrophage activation.  J Clin Invest. 2006;  116 2044-2055
    CrossrefPubMedGoogle Scholar
  • 86 Reiman R M, Thompson R W, Feng C G et al.. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity.  Infect Immun. 2006;  74 1471-1479
    CrossrefPubMedGoogle Scholar
  • 87 Weng H L, Liu Y, Chen J L et al.. The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis.  Hepatology. 2009;  50 230-243
    CrossrefPubMedGoogle Scholar
  • 88 Hesse M, Cheever A W, Jankovic D, Wynn T A. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease.  Am J Pathol. 2000;  157 945-955
    CrossrefPubMedGoogle Scholar
  • 89 Hesse M, Modolell M, La Flamme A C et al.. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism.  J Immunol. 2001;  167 6533-6544
    PubMedGoogle Scholar
  • 90 Gordon S. Alternative activation of macrophages.  Nat Rev Immunol. 2003;  3 23-35
    CrossrefPubMedGoogle Scholar
  • 91 Pesce J T, Ramalingam T R, Mentink-Kane M M et al.. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.  PLoS Pathog. 2009;  5 e1000371
    CrossrefPubMedGoogle Scholar
  • 92 Song E, Ouyang N, Hörbelt M, Antus B, Wang M, Exton M S. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts.  Cell Immunol. 2000;  204 19-28
    CrossrefPubMedGoogle Scholar
  • 93 Goerdt S, Orfanos C E. Other functions, other genes: alternative activation of antigen-presenting cells.  Immunity. 1999;  10 137-142
    CrossrefPubMedGoogle Scholar
  • 94 Doyle A G, Herbein G, Montaner L J et al.. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-gamma.  Eur J Immunol. 1994;  24 1441-1445
    CrossrefPubMedGoogle Scholar
  • 95 Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.  J Exp Med. 1992;  176 287-292
    Google Scholar
  • 96 Gordon S. Macrophages and the immune response. In: Paul WE Fundamental Immunology. Philadelphia; Lippincott-Raven Publishers 1999: 533-544
    PubMedGoogle Scholar
  • 97 Modolell M, Corraliza I M, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines.  Eur J Immunol. 1995;  25 1101-1104
    CrossrefPubMedGoogle Scholar
  • 98 Schebesch C, Kodelja V, Müller C et al.. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro.  Immunology. 1997;  92 478-486
    CrossrefPubMedGoogle Scholar
  • 99 MacLeod C L. Regulation of cationic amino acid transporter (CAT) gene expression.  Biochem Soc Trans. 1996;  24 846-852
    PubMedGoogle Scholar
  • 100 Gangadharan B, Hoeve M A, Allen J E et al.. Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages.  J Leukoc Biol. 2008;  84 50-58
    CrossrefPubMedGoogle Scholar
  • 101 Migliaccio C T, Buford M C, Jessop F, Holian A. The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosis.  J Leukoc Biol. 2008;  83 630-639
    CrossrefPubMedGoogle Scholar
  • 102 Prasse A, Pechkovsky D V, Toews G B et al.. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18.  Am J Respir Crit Care Med. 2006;  173 781-792
    CrossrefPubMedGoogle Scholar
  • 103 El Kasmi K C, Qualls J E, Pesce J T et al.. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.  Nat Immunol. 2008;  9 1399-1406
    CrossrefPubMedGoogle Scholar
  • 104 Frey A B. Myeloid suppressor cells regulate the adaptive immune response to cancer.  J Clin Invest. 2006;  116 2587-2590
    CrossrefPubMedGoogle Scholar
  • 105 Loke P, Nair M G, Guiliano D et al.. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype.  Biomed Central. 2002;  3 7
    PubMedGoogle Scholar
  • 106 Raes G, Baetselier P D, Noel W et al.. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages.  J Leukoc Biol. 2002;  71 597-602
    PubMedGoogle Scholar
  • 107 Sandler N G, Mentink-Kane M M, Cheever A W, Wynn T A. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair.  J Immunol. 2003;  171 3655-3667
    PubMedGoogle Scholar
  • 108 Holcomb I N, Kabakoff R C, Chan B et al.. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.  EMBO J. 2000;  19 4046-4055
    CrossrefPubMedGoogle Scholar
  • 109 Gerstmayer B, Küsters D, Gebel S et al.. Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern.  Genomics. 2003;  81 588-595
    CrossrefPubMedGoogle Scholar
  • 110 Bełtowski J. Adiponectin and resistin—new hormones of white adipose tissue.  Med Sci Monit. 2003;  9 RA55-RA61
    PubMedGoogle Scholar
  • 111 Liu T, Jin H, Ullenbruch M et al.. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6.  J Immunol. 2004;  173 3425-3431
    PubMedGoogle Scholar
  • 112 Stütz A M, Pickart L A, Trifilieff A, Baumruker T, Prieschl-Strassmayr E, Woisetschläger M. The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism.  J Immunol. 2003;  170 1789-1796
    PubMedGoogle Scholar
  • 113 Nair M G, Cochrane D W, Allen J E. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro.  Immunol Lett. 2003;  85 173-180
    CrossrefPubMedGoogle Scholar
  • 114 Edwards J P, Zhang X, Frauwirth K A, Mosser D M. Biochemical and functional characterization of three activated macrophage populations.  J Leukoc Biol. 2006;  80 1298-1307
    CrossrefPubMedGoogle Scholar
  • 115 Raes G, Noël W, Beschin A, Brys L, de Baetselier P, Hassanzadeh G H. FIZZ1 and Ym as tools to discriminate between differentially activated macrophages.  Dev Immunol. 2002;  9 151-159
    CrossrefPubMedGoogle Scholar
  • 116 Liu T, Dhanasekaran S M, Jin H et al.. FIZZ1 stimulation of myofibroblast differentiation.  Am J Pathol. 2004;  164 1315-1326
    CrossrefPubMedGoogle Scholar
  • 117 Liu T, Hu B, Choi Y Y et al.. Notch1 signaling in FIZZ1 induction of myofibroblast differentiation.  Am J Pathol. 2009;  174 1745-1755
    CrossrefPubMedGoogle Scholar
  • 118 Chung M J, Liu T, Ullenbruch M, Phan S H. Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts.  J Pathol. 2007;  212 180-187
    CrossrefPubMedGoogle Scholar
  • 119 Mishra A, Wang M, Schlotman J et al.. Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung.  Am J Physiol Lung Cell Mol Physiol. 2007;  293 L305-L313
    CrossrefPubMedGoogle Scholar
  • 120 Anthony R M, Urban Jr J F, Alem F et al.. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites.  Nat Med. 2006;  12 955-960
    CrossrefPubMedGoogle Scholar
  • 121 Loke P, Gallagher I, Nair M G et al.. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection.  J Immunol. 2007;  179 3926-3936
    PubMedGoogle Scholar
  • 122 Reece J J, Siracusa M C, Scott A L. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages.  Infect Immun. 2006;  74 4970-4981
    CrossrefPubMedGoogle Scholar
  • 123 Anthony R M, Rutitzky L I, Urban Jr J F, Stadecker M J, Gause W C. Protective immune mechanisms in helminth infection.  Nat Rev Immunol. 2007;  7 975-987
    CrossrefPubMedGoogle Scholar
  • 124 Wilson M S, Mentink-Kane M M, Pesce J T, Ramalingam T R, Thompson R, Wynn T A. Immunopathology of schistosomiasis.  Immunol Cell Biol. 2007;  85 148-154
    CrossrefPubMedGoogle Scholar
  • 125 Nair M G, Gallagher I J, Taylor M D et al.. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells.  Infect Immun. 2005;  73 385-394
    CrossrefPubMedGoogle Scholar
  • 126 Pesce J T, Ramalingam T R, Wilson M S et al.. Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.  PLoS Pathog. 2009;  5 e1000393
    CrossrefPubMedGoogle Scholar
  • 127 Nair M G, Du Y, Perrigoue J G et al.. Alternatively activated macrophage-derived RELM-alpha is a negative regulator of type 2 inflammation in the lung.  J Exp Med. 2009;  206 937-952
    CrossrefPubMedGoogle Scholar
  • 128 Guan S P, Mok Y K, Koo K N, Chu K L, Wong W S. Chitinases: biomarkers for human diseases.  Protein Pept Lett. 2009;  16 490-498
    CrossrefPubMedGoogle Scholar
  • 129 Sutherland T E, Maizels R M, Allen J E. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies.  Clin Exp Allergy. 2009;  39 943-955
    CrossrefPubMedGoogle Scholar
  • 130 Reese T A, Liang H E, Tager A M et al.. Chitin induces accumulation in tissue of innate immune cells associated with allergy.  Nature. 2007;  447 92-96
    CrossrefPubMedGoogle Scholar
  • 131 Zhu Z, Zheng T, Homer R J et al.. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation.  Science. 2004;  304 1678-1682
    CrossrefPubMedGoogle Scholar
  • 132 Lee C G, Hartl D, Lee G R et al.. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis.  J Exp Med. 2009;  206 1149-1166
    CrossrefPubMedGoogle Scholar
  • 133 Boot R G, Renkema G H, Strijland A, van Zonneveld A J, Aerts J M. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages.  J Biol Chem. 1995;  270 26252-26256
    CrossrefPubMedGoogle Scholar
  • 134 Malaguarnera L. Chitotriosidase: the yin and yang.  Cell Mol Life Sci. 2006;  63 3018-3029
    CrossrefPubMedGoogle Scholar
  • 135 Malaguarnera L, Di Rosa M, Zambito A M, dell'Ombra N, Nicoletti F, Malaguarnera M. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease.  Gut. 2006;  55 1313-1320
    CrossrefPubMedGoogle Scholar
  • 136 Malaguarnera L, Rosa M D, Zambito A M, dell'Ombra N, Marco R D, Malaguarnera M. Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution.  Am J Gastroenterol. 2006;  101 2060-2069
    CrossrefPubMedGoogle Scholar
  • 137 Bargagli E, Margollicci M, Luddi A et al.. Chitotriosidase activity in patients with interstitial lung diseases.  Respir Med. 2007;  101 2176-2181
    CrossrefPubMedGoogle Scholar
  • 138 Tercelj M, Salobir B, Simcic S, Wraber B, Zupancic M, Rylander R. Chitotriosidase activity in sarcoidosis and some other pulmonary diseases.  Scand J Clin Lab Invest. 2009;  69 575-578
    CrossrefPubMedGoogle Scholar
  • 139 Tran A, Benzaken S, Saint-Paul M C et al.. Chondrex (YKL-40), a potential new serum fibrosis marker in patients with alcoholic liver disease.  Eur J Gastroenterol Hepatol. 2000;  12 989-993
    CrossrefPubMedGoogle Scholar
  • 140 Johansen J S, Krabbe K S, Møller K, Pedersen B K. Circulating YKL-40 levels during human endotoxaemia.  Clin Exp Immunol. 2005;  140 343-348
    CrossrefPubMedGoogle Scholar
  • 141 Junker N, Johansen J S, Andersen C B, Kristjansen P E. Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer.  Lung Cancer. 2005;  48 223-231
    CrossrefPubMedGoogle Scholar
  • 142 Johansen J S, Milman N, Hansen M, Garbarsch C, Price P A, Graudal N. Increased serum YKL-40 in patients with pulmonary sarcoidosis—a potential marker of disease activity?.  Respir Med. 2005;  99 396-402
    CrossrefPubMedGoogle Scholar
  • 143 Hoffmann K F, McCarty T C, Segal D H et al.. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions.  FASEB J. 2001;  15 2545-2547
    PubMedGoogle Scholar
  • 144 Troidl C, Möllmann H, Nef H et al.. Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction.  J Cell Mol Med. 2009;  13 3485-3496
    CrossrefPubMedGoogle Scholar
  • 145 Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.  J Immunol. 1998;  160 5347-5354
    PubMedGoogle Scholar
  • 146 Morris Jr S M, Kepka-Lenhart D, Chen L C. Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells.  Am J Physiol. 1998;  275(5 Pt 1) E740-E747
    PubMedGoogle Scholar
  • 147 Dunn M A, Rojkind M, Warren K S, Hait P K, Rifas L, Seifter S. Liver collagen synthesis in murine schistosomiasis.  J Clin Invest. 1977;  59 666-674
    CrossrefPubMedGoogle Scholar
  • 148 Shearer J D, Richards J R, Mills C D, Caldwell M D. Differential regulation of macrophage arginine metabolism: a proposed role in wound healing.  Am J Physiol. 1997;  272(2 Pt 1) E181-E190
    PubMedGoogle Scholar
  • 149 Endo M, Oyadomari S, Terasaki Y et al.. Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung.  Am J Physiol Lung Cell Mol Physiol. 2003;  285 L313-L321
    PubMedGoogle Scholar
  • 150 Desguerre I, Mayer M, Leturcq F, Barbet J P, Gherardi R K, Christov C. Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation.  J Neuropathol Exp Neurol. 2009;  68 762-773
    CrossrefPubMedGoogle Scholar
  • 151 Herbert D R, Hölscher C, Mohrs M et al.. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.  Immunity. 2004;  20 623-635
    CrossrefPubMedGoogle Scholar
  • 152 Yang M, Rangasamy D, Matthaei K I et al.. Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness.  J Immunol. 2006;  177 5595-5603
    PubMedGoogle Scholar
  • 153 Zhao A, Urban Jr J F, Anthony R M et al.. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages.  Gastroenterology. 2008;  135 217-225
    CrossrefPubMedGoogle Scholar
  • 154 Abbas A K, Murphy K M, Sher A. Functional diversity of helper T lymphocytes.  Nature. 1996;  383 787-793
    CrossrefPubMedGoogle Scholar
  • 155 Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism.  Nat Rev Immunol. 2005;  5 641-654
    CrossrefPubMedGoogle Scholar
  • 156 Gallina G, Dolcetti L, Serafini P et al.. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.  J Clin Invest. 2006;  116 2777-2790
    CrossrefPubMedGoogle Scholar
  • 157 Rodriguez P C, Quiceno D G, Zabaleta J et al.. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.  Cancer Res. 2004;  64 5839-5849
    CrossrefPubMedGoogle Scholar
  • 158 Mills C D, Kincaid K, Alt J M, Heilman M J, Hill A M. M-1/M-2 macrophages and the Th1/Th2 paradigm.  J Immunol. 2000;  164 6166-6173
    Google Scholar
  • 159 Segawa M, Fukada S, Yamamoto Y et al.. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis.  Exp Cell Res. 2008;  314 3232-3244
    CrossrefPubMedGoogle Scholar
  • 160 Zimmermann N, King N E, Laporte J et al.. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis.  J Clin Invest. 2003;  111 1863-1874
    CrossrefPubMedGoogle Scholar
  • 161 Nishida M, Okumura Y, Fujimoto S, Shiraishi I, Itoi T, Hamaoka K. Adoptive transfer of macrophages ameliorates renal fibrosis in mice.  Biochem Biophys Res Commun. 2005;  332 11-16
    CrossrefPubMedGoogle Scholar
  • 162 Harty M W, Papa E F, Huddleston H M et al.. Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers.  Surgery. 2008;  143 667-678
    CrossrefPubMedGoogle Scholar
  • 163 Mitchell C, Couton D, Couty J P et al.. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice.  Am J Pathol. 2009;  174 1766-1775
    CrossrefPubMedGoogle Scholar
  • 164 Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride.  J Appl Toxicol. 2003;  23 103-108
    CrossrefPubMedGoogle Scholar
  • 165 Roggin K K, Papa E F, Kurkchubasche A G, Tracy Jr T F. Kupffer cell inactivation delays repair in a rat model of reversible biliary obstruction.  J Surg Res. 2000;  90 166-173
    CrossrefPubMedGoogle Scholar
  • 166 Fallowfield J A, Mizuno M, Kendall T J et al.. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis.  J Immunol. 2007;  178 5288-5295
    CrossrefPubMedGoogle Scholar
  • 167 Madala S K, Pesce J T, Ramalingam T R et al.. Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis.  J Immunol. 2010;  184 3955-3963
    CrossrefPubMedGoogle Scholar
  • 168 Cabrera S, Gaxiola M, Arreola J L et al.. Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin.  Int J Biochem Cell Biol. 2007;  39 2324-2338
    CrossrefPubMedGoogle Scholar
  • 169 Hironaka K, Sakaida I, Matsumura Y, Kaino S, Miyamoto K, Okita K. Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig serum-induced rat liver fibrosis.  Biochem Biophys Res Commun. 2000;  267 290-295
    CrossrefPubMedGoogle Scholar
  • 170 Uchinami H, Seki E, Brenner D A, D'Armiento J. Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis.  Hepatology. 2006;  44 420-429
    CrossrefPubMedGoogle Scholar
  • 171 Imamura M, Ogawa T, Sasaguri Y, Chayama K, Ueno H. Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats.  Gastroenterology. 2005;  128 138-146
    CrossrefPubMedGoogle Scholar
  • 172 Gross T J, Hunninghake G W. Idiopathic pulmonary fibrosis.  N Engl J Med. 2001;  345 517-525
    CrossrefPubMedGoogle Scholar
  • 173 Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis.  Lancet. 2006;  367 241-251
    CrossrefPubMedGoogle Scholar
  • 174 Berenguer M, Aguilera V, Prieto M et al.. Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression.  J Hepatol. 2006;  44 717-722
    CrossrefPubMedGoogle Scholar
  • 175 Issa R, Zhou X, Trim N et al.. Mutation in collagen-1 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.  FASEB J. 2003;  17 47-49
    PubMedGoogle Scholar

Thomas A WynnPh.D. 

Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Bethesda, MD 20892

Email: twynn@niaid.nih.gov

      >