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Macrophage Plasticity in Skin Fibrosis

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Fibrosis in Disease

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

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Abstract

Macrophages are highly plastic cells of myeloid origin which are causative for several diseases. In the past two decades, macrophages have been studied for their involvement in various forms of skin fibrosis. This includes hypertrophic scarring following burn, radiation and trauma injuries, rare diseases such as scleroderma, and the foreign body response evoked in response to subcutaneously implanted biomaterials. The extent of fibrosis can be correlated with alterations in macrophage number and a deviation in their spatial and temporal function. However, identifying the predominant macrophage function at a given time and determining aberrations have been difficult due to the numerous characteristics acquired by these unique cells, also referred to as macrophage heterogeneity. These functions include but are not limited to phagocytosis, production of reactive oxygen species and inflammatory cytokines, deposition of extracellular matrix, lysis of extracellular matrix, production of regenerative cytokines, blood vessel fusion, and macrophage self-fusion to form multinucleated giant cells. By performing these functions, macrophages exert influences on other stromal cells such as fibroblasts and endothelial cells and immune cells such as T-lymphocytes and the ECM itself. Some of the influences are desirable and necessary for healing, which implies that depletion of macrophages cannot be a simple solution to preventing fibrosis. Here, we will address changing macrophage phenotypes in skin fibrosis and the influence that macrophage ontogeny, epigenetic factors, and the microenvironment exert on these phenotypes. A more thorough understanding will aid in the discovery of unique biomarkers for fibrosis and in the development of targeted therapies.

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References

  1. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64. https://doi.org/10.1038/nri1733.

    Article  CAS  PubMed  Google Scholar 

  2. Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91. https://doi.org/10.1016/j.immuni.2012.12.001.

    Article  CAS  PubMed  Google Scholar 

  3. Hashimoto D, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792–804. https://doi.org/10.1016/j.immuni.2013.04.004.

    Article  CAS  PubMed  Google Scholar 

  4. Gomez Perdiguero E, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51. https://doi.org/10.1038/nature13989.

    Article  CAS  PubMed  Google Scholar 

  5. Schulz C, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336:86–90. https://doi.org/10.1126/science.1219179.

    Article  CAS  PubMed  Google Scholar 

  6. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14:986–95. https://doi.org/10.1038/ni.2705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosas M, et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science. 2014;344:645–8. https://doi.org/10.1126/science.1251414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ginhoux F, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–5. https://doi.org/10.1126/science.1194637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392–404. https://doi.org/10.1038/nri3671.

    Article  CAS  PubMed  Google Scholar 

  10. Gordon S, Pluddemann A, Martinez Estrada F. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev. 2014;262:36–55. https://doi.org/10.1111/imr.12223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55. https://doi.org/10.1038/nature12034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Murray PJ, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20. https://doi.org/10.1016/j.immuni.2014.06.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13. https://doi.org/10.12703/P6-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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;176:287–92.

    Article  CAS  PubMed  Google Scholar 

  15. Nahrendorf M, Swirski FK. Abandoning M1/M2 for a network model of macrophage function. Circ Res. 2016;119:414–7. https://doi.org/10.1161/CIRCRESAHA.116.309194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodrigues M, Geoffrey GC. Black, white and gray: macrophages in skin repair and disease. Curr Pathobiol Rep. 2017;5:333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–21. https://doi.org/10.1038/nature07039.

    Article  CAS  PubMed  Google Scholar 

  18. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2018. [In Press].

    Google Scholar 

  19. Weidenbusch M, Anders HJ. Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J Innate Immun. 2012;4:463–77. https://doi.org/10.1159/000336717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20. https://doi.org/10.1016/j.cell.2010.01.022.

    Article  CAS  PubMed  Google Scholar 

  21. DiPietro LA, Polverini PJ, Rahbe SM, Kovacs EJ. Modulation of JE/MCP-1 expression in dermal wound repair. Am J Pathol. 1995;146:868–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dipietro LA, Reintjes MG, Low QE, Levi B, Gamelli RL. Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein-1. Wound Repair Regen. 2001;9:28–33.

    Article  CAS  PubMed  Google Scholar 

  23. Slauch JM. How does the oxidative burst of macrophages kill bacteria? Still an open question. Mol Microbiol. 2011;80:580–3. https://doi.org/10.1111/j.1365-2958.2011.07612.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin P. Wound healing – aiming for perfect skin regeneration. Science. 1997;276:75–81.

    Article  CAS  PubMed  Google Scholar 

  25. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784–8. https://doi.org/10.1038/35037722.

    Article  CAS  PubMed  Google Scholar 

  26. Bratton DL, Henson PM. Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol. 2011;32:350–7. https://doi.org/10.1016/j.it.2011.04.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen WY, Rogers AA. Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds. Wound Repair Regen. 2007;15:434–49. https://doi.org/10.1111/j.1524-475X.2007.00250.x.

    Article  PubMed  Google Scholar 

  28. Willenborg S, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120:613–25. https://doi.org/10.1182/blood-2012-01-403386.

    Article  CAS  PubMed  Google Scholar 

  29. Fantin A, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116:829–40. https://doi.org/10.1182/blood-2009-12-257832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Outtz HH, Tattersall IW, Kofler NM, Steinbach N, Kitajewski J. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood. 2011;118:3436–9. https://doi.org/10.1182/blood-2010-12-327015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Okuno Y, Nakamura-Ishizu A, Kishi K, Suda T, Kubota Y. Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing. Blood. 2011;117:5264–72. https://doi.org/10.1182/blood-2011-01-330720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rohde E, et al. Blood monocytes mimic endothelial progenitor cells. Stem Cells. 2006;24:357–67. https://doi.org/10.1634/stemcells.2005-0072.

    Article  PubMed  Google Scholar 

  33. Yamaguchi Y, et al. Enhanced angiogenic potency of monocytic endothelial progenitor cells in patients with systemic sclerosis. Arthritis Res Ther. 2010;12:R205. https://doi.org/10.1186/ar3180.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yamaguchi Y, Kuwana M. Proangiogenic hematopoietic cells of monocytic origin: roles in vascular regeneration and pathogenic processes of systemic sclerosis. Histol Histopathol. 2013;28:175–83. https://doi.org/10.14670/HH-28.175.

    Article  CAS  PubMed  Google Scholar 

  35. Zhu Z, Ding J, Ma Z, Iwashina T, Tredget EE. Alternatively activated macrophages derived from THP-1 cells promote the fibrogenic activities of human dermal fibroblasts. Wound Repair Regen. 2017; https://doi.org/10.1111/wrr.12532.

    Article  PubMed  Google Scholar 

  36. Shook B, Xiao E, Kumamoto Y, Iwasaki A, Horsley V. CD301b+ macrophages are essential for effective skin wound healing. J Invest Dermatol. 2016;136:1885–91. https://doi.org/10.1016/j.jid.2016.05.107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Suga H, et al. Tracking the elusive fibrocyte: identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing. Stem Cells. 2014;32:1347–60. https://doi.org/10.1002/stem.1648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reilkoff RA, Bucala R, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol. 2011;11:427–35. https://doi.org/10.1038/nri2990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Duscher D, et al. Mechanotransduction and fibrosis. J Biomech. 2014;47:1997–2005. https://doi.org/10.1016/j.jbiomech.2014.03.031.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wong VW, et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med. 2011;18:148–52. https://doi.org/10.1038/nm.2574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rinkevich Y, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015;348:aaa2151. https://doi.org/10.1126/science.aaa2151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Huang C, et al. Keloid progression: a stiffness gap hypothesis. Int Wound J. 2017;14:764–71. https://doi.org/10.1111/iwj.12693.

    Article  PubMed  Google Scholar 

  43. Kraling BM, Maul GG, Jimenez SA. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;63:48–56.

    Article  CAS  PubMed  Google Scholar 

  44. Ishikawa O, Ishikawa H. Macrophage infiltration in the skin of patients with systemic sclerosis. J Rheumatol. 1992;19:1202–6.

    CAS  PubMed  Google Scholar 

  45. Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med. 2007;4:e234. https://doi.org/10.1371/journal.pmed.0040234.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chatzizisis YS, et al. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007;49:2379–93. https://doi.org/10.1016/j.jacc.2007.02.059.

    Article  CAS  PubMed  Google Scholar 

  47. Ventrice EA, et al. Molecular and biophysical mechanisms and modulation of ventilator-induced lung injury. Med Intensiva. 2007;31:73–82.

    Article  CAS  PubMed  Google Scholar 

  48. Kwon SH, et al. Prevention of venous neointimal hyperplasia by a multitarget receptor tyrosine kinase inhibitor. J Vasc Res. 2015;52:244–56. https://doi.org/10.1159/000442977.

    Article  CAS  PubMed  Google Scholar 

  49. Major MR, Wong VW, Nelson ER, Longaker MT, Gurtner GC. The foreign body response: at the interface of surgery and bioengineering. Plast Reconstr Surg. 2015;135:1489–98. https://doi.org/10.1097/PRS.0000000000001193.

    Article  CAS  PubMed  Google Scholar 

  50. Rennert RC, et al. A histological and mechanical analysis of the cardiac lead-tissue interface: implications for lead extraction. Acta Biomater. 2014;10:2200–8. https://doi.org/10.1016/j.actbio.2014.01.008.

    Article  PubMed  Google Scholar 

  51. Ferretti M, et al. Biomechanical signals suppress proinflammatory responses in cartilage: early events in experimental antigen-induced arthritis. J Immunol. 2006;177:8757–66.

    Article  CAS  PubMed  Google Scholar 

  52. Celil Aydemir AB, et al. Nuclear factor of activated T cell mediates proinflammatory gene expression in response to mechanotransduction. Ann N Y Acad Sci. 2007;1117:138–42. https://doi.org/10.1196/annals.1402.004.

    Article  CAS  PubMed  Google Scholar 

  53. Lionetti V, Recchia FA, Ranieri VM. Overview of ventilator-induced lung injury mechanisms. Curr Opin Crit Care. 2005;11:82–6.

    Article  PubMed  Google Scholar 

  54. Knobloch TJ, Madhavan S, Nam J, Agarwal S Jr, Agarwal S. Regulation of chondrocytic gene expression by biomechanical signals. Crit Rev Eukaryot Gene Expr. 2008;18:139–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gurtner GC, et al. Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Ann Surg. 2011;254:217–25. https://doi.org/10.1097/SLA.0b013e318220b159.

    Article  PubMed  Google Scholar 

  56. Carmo-Fonseca M, Cidadao AJ, David-Ferreira JF. Filamentous cross-bridges link intermediate filaments to the nuclear pore complexes. Eur J Cell Biol. 1988;45:282–90.

    CAS  PubMed  Google Scholar 

  57. Jiang HQ, Zhang XL, Liu L, Yang CC. Relationship between focal adhesion kinase and hepatic stellate cell proliferation during rat hepatic fibrogenesis. World J Gastroenterol. 2004;10:3001–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Clemente CF, et al. Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circ Res. 2007;101:1339–48. https://doi.org/10.1161/CIRCRESAHA.107.160978.

    Article  CAS  PubMed  Google Scholar 

  59. Morla AO, Mogford JE. Control of smooth muscle cell proliferation and phenotype by integrin signaling through focal adhesion kinase. Biochem Biophys Res Commun. 2000;272:298–302. https://doi.org/10.1006/bbrc.2000.2769.

    Article  CAS  PubMed  Google Scholar 

  60. Garneau-Tsodikova S, Thannickal VJ. Protein kinase inhibitors in the treatment of pulmonary fibrosis. Curr Med Chem. 2008;15:2632–40.

    Article  CAS  PubMed  Google Scholar 

  61. Wong VW, et al. Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing. Ann Surg. 2014;260:1138–46. https://doi.org/10.1097/SLA.0000000000000219.

    Article  PubMed  Google Scholar 

  62. Liu W, et al. The abnormal architecture of healed diabetic ulcers is the result of FAK degradation by calpain 1. J Invest Dermatol. 2017;137:1155–65. https://doi.org/10.1016/j.jid.2016.11.039.

    Article  CAS  PubMed  Google Scholar 

  63. Rustad KC, Wong VW, Gurtner GC. The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation. Differentiation. 2013;86:87–91. https://doi.org/10.1016/j.diff.2013.02.003.

    Article  CAS  PubMed  Google Scholar 

  64. Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci. 2003;116:1409–16.

    Article  CAS  PubMed  Google Scholar 

  65. Ding Q, Gladson CL, Wu H, Hayasaka H, Olman MA. Focal adhesion kinase (FAK)-related non-kinase inhibits myofibroblast differentiation through differential MAPK activation in a FAK-dependent manner. J Biol Chem. 2008;283:26839–49. https://doi.org/10.1074/jbc.M803645200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Aarabi S, et al. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 2007;21:3250–61. https://doi.org/10.1096/fj.07-8218com.

    Article  CAS  PubMed  Google Scholar 

  67. Wong VW, et al. Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation. FASEB J. 2011;25:4498–510. https://doi.org/10.1096/fj.10-178087.

    Article  CAS  PubMed  Google Scholar 

  68. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chin YR, Toker A. Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal. 2009;21:470–6. https://doi.org/10.1016/j.cellsig.2008.11.015.

    Article  CAS  PubMed  Google Scholar 

  70. Nishimura K, et al. Role of AKT in cyclic strain-induced endothelial cell proliferation and survival. Am J Physiol Cell Physiol. 2006;290:C812–21. https://doi.org/10.1152/ajpcell.00347.2005.

    Article  CAS  PubMed  Google Scholar 

  71. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002;4:658–65. https://doi.org/10.1038/ncb840.

    Article  CAS  PubMed  Google Scholar 

  72. Tian B, Lessan K, Kahm J, Kleidon J, Henke C. Beta 1 integrin regulates fibroblast viability during collagen matrix contraction through a phosphatidylinositol 3-kinase/Akt/protein kinase B signaling pathway. J Biol Chem. 2002;277:24667–75. https://doi.org/10.1074/jbc.M203565200.

    Article  CAS  PubMed  Google Scholar 

  73. Hayashida T, et al. MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397. J Cell Sci. 2007;120:4230–40. https://doi.org/10.1242/jcs.03492.

    Article  CAS  PubMed  Google Scholar 

  74. Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2:717–26. https://doi.org/10.1038/nrd1177.

    Article  CAS  PubMed  Google Scholar 

  75. Tsukada S, Westwick JK, Ikejima K, Sato N, Rippe RA. SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells. J Biol Chem. 2005;280:10055–64. https://doi.org/10.1074/jbc.M409381200.

    Article  CAS  PubMed  Google Scholar 

  76. Graness A, Cicha I, Goppelt-Struebe M. Contribution of Src-FAK signaling to the induction of connective tissue growth factor in renal fibroblasts. Kidney Int. 2006;69:1341–9. https://doi.org/10.1038/sj.ki.5000296.

    Article  CAS  PubMed  Google Scholar 

  77. Wilgus TA. Immune cells in the healing skin wound: influential players at each stage of repair. Pharmacol Res. 2008;58:112–6. https://doi.org/10.1016/j.phrs.2008.07.009.

    Article  CAS  PubMed  Google Scholar 

  78. Kwon SH, Gurtner GC. Is early inflammation good or bad? Linking early immune changes to hypertrophic scarring. Exp Dermatol. 2017;26:133–4. https://doi.org/10.1111/exd.13167.

    Article  PubMed  Google Scholar 

  79. Butzelaar L, et al. Inhibited early immunologic response is associated with hypertrophic scarring. Exp Dermatol. 2016;25:797–804. https://doi.org/10.1111/exd.13100.

    Article  CAS  PubMed  Google Scholar 

  80. van den Broek LJ, van der Veer WM, de Jong EH, Gibbs S, Niessen FB. Suppressed inflammatory gene expression during human hypertrophic scar compared to normotrophic scar formation. Exp Dermatol. 2015;24:623–9. https://doi.org/10.1111/exd.12739.

    Article  CAS  PubMed  Google Scholar 

  81. Englander HR. Fluoridation protects occlusal areas. J Am Dent Assoc. 1979;98:11.

    Article  CAS  PubMed  Google Scholar 

  82. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12:1035–44. https://doi.org/10.1038/ni.2109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Goren I, et al. A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes. Am J Pathol. 2009;175:132–47. https://doi.org/10.2353/ajpath.2009.081002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol. 2009;175:2454–62. https://doi.org/10.2353/ajpath.2009.090248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Terry RL, Miller SD. Molecular control of monocyte development. Cell Immunol. 2014;291:16–21. https://doi.org/10.1016/j.cellimm.2014.02.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hettinger J, et al. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol. 2013;14:821–30. https://doi.org/10.1038/ni.2638.

    Article  CAS  PubMed  Google Scholar 

  87. Cros J, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010;33:375–86. https://doi.org/10.1016/j.immuni.2010.08.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Carlin LM, et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013;153:362–75. https://doi.org/10.1016/j.cell.2013.03.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Auffray C, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317:666–70. https://doi.org/10.1126/science.1142883.

    Article  CAS  PubMed  Google Scholar 

  90. Fernandez Pujol B, et al. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation. 2000;65:287–300.

    Article  CAS  PubMed  Google Scholar 

  91. Schmeisser A, et al. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res. 2001;49:671–80.

    Article  CAS  PubMed  Google Scholar 

  92. Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003;107:1164–9.

    Article  PubMed  Google Scholar 

  93. Satoh T, et al. Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature. 2017;541:96–101. https://doi.org/10.1038/nature20611.

    Article  CAS  PubMed  Google Scholar 

  94. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol. 2003;171:380–9.

    Article  CAS  PubMed  Google Scholar 

  95. Yang L, et al. Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Investig. 2002;82:1183–92.

    Article  CAS  PubMed  Google Scholar 

  96. Aung H, Sherman J, Tary-Lehman M, Toossi Z. Analysis of transforming growth factor-beta 1 (TGF-beta1) expression in human monocytes infected with Mycobacterium avium at a single cell level by ELISPOT assay. J Immunol Methods. 2002;259:25–32.

    Article  CAS  PubMed  Google Scholar 

  97. Lucas T, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184:3964–77. https://doi.org/10.4049/jimmunol.0903356.

    Article  CAS  PubMed  Google Scholar 

  98. MacDonald KP, et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood. 2010;116:3955–63. https://doi.org/10.1182/blood-2010-02-266296.

    Article  CAS  PubMed  Google Scholar 

  99. Maan ZN, et al. Abstract 10: global and endothelial cell specific deletion of SDF-1 results in delayed wound healing. Plast Reconstr Surg. 2014;133:20. https://doi.org/10.1097/01.prs.0000444963.66915.ba.

    Article  PubMed  Google Scholar 

  100. Lavin Y, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159:1312–26. https://doi.org/10.1016/j.cell.2014.11.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gosselin D, et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159:1327–40. https://doi.org/10.1016/j.cell.2014.11.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ghisletti S, et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010;32:317–28. https://doi.org/10.1016/j.immuni.2010.02.008.

    Article  CAS  PubMed  Google Scholar 

  103. Amit I, Winter DR, Jung S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol. 2016;17:18–25. https://doi.org/10.1038/ni.3325.

    Article  CAS  PubMed  Google Scholar 

  104. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. https://doi.org/10.1161/01.RES.0000070112.80711.3D.

    Article  CAS  PubMed  Google Scholar 

  105. Caley MP, Martins VL, O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care (New Rochelle). 2015;4:225–34. https://doi.org/10.1089/wound.2014.0581.

    Article  Google Scholar 

  106. Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995;146:56–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lech M, Anders HJ. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta. 2013;1832:989–97. https://doi.org/10.1016/j.bbadis.2012.12.001.

    Article  CAS  PubMed  Google Scholar 

  108. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83. https://doi.org/10.1146/annurev.immunol.021908.132532.

    Article  CAS  PubMed  Google Scholar 

  109. Wernig G, et al. Unifying mechanism for different fibrotic diseases. Proc Natl Acad Sci U S A. 2017;114:4757–62. https://doi.org/10.1073/pnas.1621375114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Weissman I. Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370:20140364. https://doi.org/10.1098/rstb.2014.0364.

    Article  CAS  Google Scholar 

  111. Gholamin S, et al. Disrupting the CD47-SIRPalpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med. 2017;9:eaaf2968. https://doi.org/10.1126/scitranslmed.aaf2968.

    Article  CAS  PubMed  Google Scholar 

  112. Kojima Y, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016;536:86–90. https://doi.org/10.1038/nature18935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Weiskopf K, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016;126:2610–20. https://doi.org/10.1172/JCI81603.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Liu J, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10:e0137345. https://doi.org/10.1371/journal.pone.0137345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. McKeown S, Richter AG, O’Kane C, McAuley DF, Thickett DR. MMP expression and abnormal lung permeability are important determinants of outcome in IPF. Eur Respir J. 2009;33:77–84. https://doi.org/10.1183/09031936.00060708.

    Article  CAS  PubMed  Google Scholar 

  116. Gill SE, Pape MC, Khokha R, Watson AJ, Leco KJ. A null mutation for tissue inhibitor of metalloproteinases-3 (Timp-3) impairs murine bronchiole branching morphogenesis. Dev Biol. 2003;261:313–23.

    Article  CAS  PubMed  Google Scholar 

  117. Telgenhoff D, Shroot B. Cellular senescence mechanisms in chronic wound healing. Cell Death Differ. 2005;12:695–8. https://doi.org/10.1038/sj.cdd.4401632.

    Article  CAS  PubMed  Google Scholar 

  118. Agostini C, et al. Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. Am J Pathol. 2001;158:1703–11. https://doi.org/10.1016/S0002-9440(10)64126-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Torraca V, et al. The CXCR3-CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection. Dis Model Mech. 2015;8:253–69. https://doi.org/10.1242/dmm.017756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yates CC, et al. Lack of CXC chemokine receptor 3 signaling leads to hypertrophic and hypercellular scarring. Am J Pathol. 2010;176:1743–55. https://doi.org/10.2353/ajpath.2010.090564.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Huen AC, Wells A. The beginning of the end: CXCR3 signaling in late-stage wound healing. Adv Wound Care (New Rochelle). 2012;1:244–8. https://doi.org/10.1089/wound.2011.0355.

    Article  Google Scholar 

  122. Bodnar RJ, Yates CC, Wells A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res. 2006;98:617–25. https://doi.org/10.1161/01.RES.0000209968.66606.10.

    Article  CAS  PubMed  Google Scholar 

  123. Shiraha H, Glading A, Chou J, Jia Z, Wells A. Activation of m-calpain (calpain II) by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain. Mol Cell Biol. 2002;22:2716–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yates CC, Whaley D, Wells A. Transplanted fibroblasts prevents dysfunctional repair in a murine CXCR3-deficient scarring model. Cell Transplant. 2012;21:919–31. https://doi.org/10.3727/096368911X623817.

    Article  PubMed  Google Scholar 

  125. Yates CC, et al. Multipotent stromal cells/mesenchymal stem cells and fibroblasts combine to minimize skin hypertrophic scarring. Stem Cell Res Ther. 2017;8:193. https://doi.org/10.1186/s13287-017-0644-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Petrovic-Djergovic D, et al. CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis. Clin Exp Immunol. 2015;180:305–15. https://doi.org/10.1111/cei.12579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Silver RM. Clinical aspects of systemic sclerosis (scleroderma). Ann Rheum Dis. 1991;50(Suppl 4):854–61.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Giuggioli D, Manfredi A, Lumetti F, Colaci M, Ferri C. Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature. Autoimmun Rev. 2018;17:155–64. https://doi.org/10.1016/j.autrev.2017.11.020.

    Article  PubMed  Google Scholar 

  129. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390:1685–99. https://doi.org/10.1016/S0140-6736(17)30933-9.

    Article  PubMed  Google Scholar 

  130. Leroy EC, Smith EA, Kahaleh MB, Trojanowska M, Silver RM. A strategy for determining the pathogenesis of systemic sclerosis. Is transforming growth factor beta the answer? Arthritis Rheum. 1989;32:817–25.

    CAS  PubMed  Google Scholar 

  131. Roumm AD, Whiteside TL, Medsger TA Jr, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27:645–53.

    Article  CAS  PubMed  Google Scholar 

  132. Hasegawa M, Sato S, Takehara K. Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis. Clin Exp Immunol. 1999;117:159–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Higashi-Kuwata N, Makino T, Inoue Y, Takeya M, Ihn H. Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma. Exp Dermatol. 2009;18:727–9. https://doi.org/10.1111/j.1600-0625.2008.00828.x.

    Article  PubMed  Google Scholar 

  134. Higashi-Kuwata N, et al. Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther. 2010;12:R128. https://doi.org/10.1186/ar3066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Koch AE, et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest. 1992;90:772–9. https://doi.org/10.1172/JCI115950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Antoniades HN, et al. Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 1992;89:5371–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Andrews BS, et al. Changes in circulating monocytes in patients with progressive systemic sclerosis. J Rheumatol. 1987;14:930–5.

    CAS  PubMed  Google Scholar 

  138. Mathai SK, et al. Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab Investig. 2010;90:812–23. https://doi.org/10.1038/labinvest.2010.73.

    Article  CAS  PubMed  Google Scholar 

  139. Mathes AL, et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann Rheum Dis. 2014;73:1864–72. https://doi.org/10.1136/annrheumdis-2012-202814.

    Article  CAS  PubMed  Google Scholar 

  140. Bielecki M, Kowal K, Lapinska A, Chyczewski L, Kowal-Bielecka O. Increased release of soluble CD163 by the peripheral blood mononuclear cells is associated with worse prognosis in patients with systemic sclerosis. Adv Med Sci. 2013;58:126–33. https://doi.org/10.2478/v10039-012-0076-9.

    Article  CAS  PubMed  Google Scholar 

  141. Kowal-Bielecka O, et al. High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis. Arthritis Res Ther. 2013;15:R69. https://doi.org/10.1186/ar4246.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Nakayama W, et al. CD163 expression is increased in the involved skin and sera of patients with systemic lupus erythematosus. Eur J Dermatol. 2012;22:512–7. https://doi.org/10.1684/ejd.2012.1756.

    Article  CAS  PubMed  Google Scholar 

  143. Nakayama W, et al. Serum levels of soluble CD163 in patients with systemic sclerosis. Rheumatol Int. 2012;32:403–7. https://doi.org/10.1007/s00296-010-1691-z.

    Article  CAS  PubMed  Google Scholar 

  144. Shimizu K, et al. Increased serum levels of soluble CD163 in patients with scleroderma. Clin Rheumatol. 2012;31:1059–64. https://doi.org/10.1007/s10067-012-1972-x.

    Article  PubMed  Google Scholar 

  145. Grigoryev DN, et al. Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res. 2008;151:197–207. https://doi.org/10.1016/j.trsl.2007.12.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Duan H, et al. Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma. Arthritis Rheum. 2008;58:1465–74. https://doi.org/10.1002/art.23451.

    Article  CAS  PubMed  Google Scholar 

  147. Christmann RB, et al. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum. 2011;63:1718–28. https://doi.org/10.1002/art.30318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Pendergrass SA, et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One. 2010;5:e12106. https://doi.org/10.1371/journal.pone.0012106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Taroni JN, et al. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med. 2017;9:27. https://doi.org/10.1186/s13073-017-0417-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kenneth Ward W. A review of the foreign-body response to subcutaneously-implanted devices: the role of macrophages and cytokines in biofouling and fibrosis. J Diabetes Sci Technol. 2008;2:768–77. https://doi.org/10.1177/193229680800200504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100. https://doi.org/10.1016/j.smim.2007.11.004.

    Article  CAS  PubMed  Google Scholar 

  152. Sheikh Z, Brooks PJ, Barzilay O, Fine N, Glogauer M. Macrophages, foreign body giant cells and their response to implantable biomaterials. Materials (Basel). 2015;8:5671–701. https://doi.org/10.3390/ma8095269.

    Article  CAS  Google Scholar 

  153. Chambers TJ, Spector WG. Inflammatory giant cells. Immunobiology. 1982;161:283–9. https://doi.org/10.1016/S0171-2985(82)80084-3.

    Article  CAS  PubMed  Google Scholar 

  154. Anderson JM. Multinucleated giant cells. Curr Opin Hematol. 2000;7:40–7.

    Article  CAS  PubMed  Google Scholar 

  155. Anderson JM, McNally AK. Biocompatibility of implants: lymphocyte/macrophage interactions. Semin Immunopathol. 2011;33:221–33. https://doi.org/10.1007/s00281-011-0244-1.

    Article  CAS  PubMed  Google Scholar 

  156. McNally AK, Jones JA, Macewan SR, Colton E, Anderson JM. Vitronectin is a critical protein adhesion substrate for IL-4-induced foreign body giant cell formation. J Biomed Mater Res A. 2008;86:535–43. https://doi.org/10.1002/jbm.a.31658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Olingy CE, et al. Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury. Sci Rep. 2017;7:447. https://doi.org/10.1038/s41598-017-00477-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. McNally AK, Anderson JM. Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am J Pathol. 2002;160:621–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wiggins MJ, Wilkoff B, Anderson JM, Hiltner A. Biodegradation of polyether polyurethane inner insulation in bipolar pacemaker leads. J Biomed Mater Res. 2001;58:302–7.

    Article  CAS  PubMed  Google Scholar 

  160. McNally AK, Anderson JM. Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells. Am J Pathol. 1995;147:1487–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. DeFife KM, Jenney CR, McNally AK, Colton E, Anderson JM. Interleukin-13 induces human monocyte/macrophage fusion and macrophage mannose receptor expression. J Immunol. 1997;158:3385–90.

    CAS  PubMed  Google Scholar 

  162. Rodriguez A, Voskerician G, Meyerson H, MacEwan SR, Anderson JM. T cell subset distributions following primary and secondary implantation at subcutaneous biomaterial implant sites. J Biomed Mater Res A. 2008;85:556–65. https://doi.org/10.1002/jbm.a.31562.

    Article  CAS  PubMed  Google Scholar 

  163. Brodbeck WG, Macewan M, Colton E, Meyerson H, Anderson JM. Lymphocytes and the foreign body response: lymphocyte enhancement of macrophage adhesion and fusion. J Biomed Mater Res A. 2005;74:222–9. https://doi.org/10.1002/jbm.a.30313.

    Article  CAS  PubMed  Google Scholar 

  164. Chang DT, Colton E, Anderson JM. Paracrine and juxtacrine lymphocyte enhancement of adherent macrophage and foreign body giant cell activation. J Biomed Mater Res A. 2009;89:490–8. https://doi.org/10.1002/jbm.a.31981.

    Article  CAS  PubMed  Google Scholar 

  165. Itescu S, Ankersmit JH, Kocher AA, Schuster MD. Immunobiology of left ventricular assist devices. Prog Cardiovasc Dis. 2000;43:67–80. https://doi.org/10.1053/pcad.2000.7191.

    Article  CAS  PubMed  Google Scholar 

  166. Rodriguez A, Macewan SR, Meyerson H, Kirk JT, Anderson JM. The foreign body reaction in T-cell-deficient mice. J Biomed Mater Res A. 2009;90:106–13. https://doi.org/10.1002/jbm.a.32050.

    Article  CAS  PubMed  Google Scholar 

  167. Gessner A, Mohrs K, Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol. 2005;174:1063–72.

    Article  CAS  PubMed  Google Scholar 

  168. Byrne AJ, Mathie SA, Gregory LG, Lloyd CM. Pulmonary macrophages: key players in the innate defence of the airways. Thorax. 2015;70:1189–96. https://doi.org/10.1136/thoraxjnl-2015-207020.

    Article  PubMed  Google Scholar 

  169. Byrne AJ, Maher TM, Lloyd CM. Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease? Trends Mol Med. 2016;22:303–16. https://doi.org/10.1016/j.molmed.2016.02.004.

    Article  CAS  PubMed  Google Scholar 

  170. Selman M, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136–51.

    Article  CAS  PubMed  Google Scholar 

  171. Wahl SM, McCartney-Francis N, Allen JB, Dougherty EB, Dougherty SF. Macrophage production of TGF-beta and regulation by TGF-beta. Ann N Y Acad Sci. 1990;593:188–96.

    Article  CAS  PubMed  Google Scholar 

  172. Bonner JC, Osornio-Vargas AR, Badgett A, Brody AR. 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;5:539–47. https://doi.org/10.1165/ajrcmb/5.6.539.

    Article  CAS  PubMed  Google Scholar 

  173. Dancer RC, Wood AM, Thickett DR. Metalloproteinases in idiopathic pulmonary fibrosis. Eur Respir J. 2011;38:1461–7. https://doi.org/10.1183/09031936.00024711.

    Article  CAS  PubMed  Google Scholar 

  174. Misharin AV, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214:2387–404. https://doi.org/10.1084/jem.20162152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. Kupffer cells in the liver. Compr Physiol. 2013;3:785–97. https://doi.org/10.1002/cphy.c120026.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–36. https://doi.org/10.1002/hep.22034.

    Article  CAS  PubMed  Google Scholar 

  177. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–86. https://doi.org/10.1111/j.1478-3231.2006.01342.x.

    Article  CAS  PubMed  Google Scholar 

  178. Wehr A, et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J Immunol. 2013;190:5226–36. https://doi.org/10.4049/jimmunol.1202909.

    Article  CAS  PubMed  Google Scholar 

  179. Otogawa K, 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;170:967–80. https://doi.org/10.2353/ajpath.2007.060441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Liu C, et al. Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab Investig. 2010;90:1805–16. https://doi.org/10.1038/labinvest.2010.123.

    Article  CAS  PubMed  Google Scholar 

  181. Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013;3:1473–92. https://doi.org/10.1002/cphy.c120035.

    Article  PubMed  Google Scholar 

  182. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 2002;36:200–9.

    Article  PubMed  Google Scholar 

  183. Gressner AM. Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis. Kidney Int Suppl. 1996;54:S39–45.

    CAS  PubMed  Google Scholar 

  184. Fallowfield JA, 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;178:5288–95.

    Article  CAS  PubMed  Google Scholar 

  185. Watanabe T, et al. Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride. J Hepatol. 2000;33:224–35.

    Article  CAS  PubMed  Google Scholar 

  186. Wan J, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014;59:130–42. https://doi.org/10.1002/hep.26607.

    Article  CAS  PubMed  Google Scholar 

  187. Duffield JS, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65. https://doi.org/10.1172/JCI22675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Tenenhaus M, Rennekampff H, Potenza B. The global impact of scars. Chapter 2, In: The Scar Book: Formation, Mitigation, Rehabilitation, and Prevention. Ed by: Krakowski AC and Shumaker PR. Wolters Kluwer; Philadelphia, 2017.

    Google Scholar 

  189. Driskell RR, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature. 2013;504:277–81. https://doi.org/10.1038/nature12783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Oskeritzian CA. Mast cells and wound healing. Adv Wound Care (New Rochelle). 2012;1:23–8. https://doi.org/10.1089/wound.2011.0357.

    Article  Google Scholar 

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  1. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Melanie Rodrigues & Clark A. Bonham

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  1. Melanie Rodrigues
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  2. Clark A. Bonham
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Correspondence to Melanie Rodrigues .

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Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA

    Monte S. Willis

  2. Department of Health Promotion and Development, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Nursing, Pittsburgh, PA, USA

    Cecelia C. Yates

  3. Department of Pharmacology and Department of Pathology and Lab Medicine, McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jonathan C. Schisler

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Rodrigues, M., Bonham, C.A. (2019). Macrophage Plasticity in Skin Fibrosis. In: Willis, M., Yates, C., Schisler, J. (eds) Fibrosis in Disease . Molecular and Translational Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-98143-7_3

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