The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases

Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76:509–13. Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 2014;26:192–7. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69. Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;4:344–6. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;12:677–86. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014;14:571–8. Yona S, Jung S. Monocytes: subsets, origins, fates and functions. Curr Opin Hematol. 2010;17:53–9. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37. Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology. 2006;211:609–18. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, et al. Monocyte subsets differentially employ CCR2, CCR5 and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–94. Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R, et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood. 2010;115:e10–9. Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G, et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013;153:362–75. Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010;33:375–86. Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Joynson TE, et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 2013;39:599–610. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilized two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204:3037–47. Lin SL, Castaño AP, Nowlin BT, Lupher Jr ML, Duffield JS. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol. 2009;183:6733–43. Heymann F, Trautwein C, Tacke F. Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets. 2009;8:307–18. Mirza R, Koh TJ. Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine. 2011;56:256–64. Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardi M, Caelles C, Serrano AL, et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol. 2011;195:307–22. Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120:613–25. Osterholzer JJ, Olszewski MA, Murdock BJ, Chen GH, Erb-Downward JR, Subbotina N, et al. Implicating exudate macrophages and Ly-6C(high) monocytes in CCR2-dependent lung fibrosis following gene-targeted alveolar injury. J Immunol. 2013;190:3447–57. Zaslona Z, Przybranowski S, Wilke C, van Rooijen N, Teitz-Tennenbaum S, Osterholzer JJ, et al. Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol. 2014;193:4245–53. Lenzo JC, Turner AL, Cook AD, Vlahos R, Anderson GP, Reynolds EC, et al. Control of macrophage lineage populations by CSF-1 receptor and GM-CSF in homeostasis and inflammation. Immunol Cell Biol. 2012;90:429–40. Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514. Sindrilaru A, Sharffetter-Kochanek K. Disclosure of the culprits: Macrophages – versatile regulators of wound healing. Adv Wound Care (New Rochelle). 2013;2:357–68. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35. Gordon S, Mantovani A. Diversity and plasticity of mononuclear phagocytes. Eur J Immunol. 2014;41:2470–2. Murray PJ, Wynn TA. Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol. 2011;89:557–63. Ferrante CJ, Liebovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care. 2012;1:10–6. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–61. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83. Vogel DY, Glim JE, Stavenuiter AW, Breur M, Heimjen P, Amor S, et al. Human macrophage polarization in vitro: maturation and activation methods compared. Immunobiology. 2014;219:695–703. Chow A, Brown BD, Merad M. Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol. 2011;11:788–98. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–88. Beyer M, Mallmann MR, Xue K, Staratschek-Jox A, Vorholt D, Krebs W, et al. High-resolution transcriptome of human macrophages. PLoS One. 2012;7:e45466. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophage. Nat Immunol. 2012;13:1118–28. Kim CC, Lanier LL. Beyond the transcriptome: completion of act one of the Immunological Genome Project. Curr Opin Immunol. 2013;25:593–7. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol. 2012;13:888–99. Poland GA, Quill H, Togias A. Understanding the human immune system in the 21st century: the Human Immunology Project Consortium. Vaccine. 2013;31:2911–2. Eigsti RL. Sudan B, Wilson ME, Graff JW. Regulation of activation-associated microRNA accumulation rates during monocyte-to-macrophage differentiation. J Biol Chem. 2014; [Epub ahead of print] Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14:986–95. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41:21–35. Okabe Y, Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014;157:832–44. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336:86–90. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792–804. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14:1142–9. Molawi K, Wolf Y, Kandalla PK, Favret J, Hagemeyer N, Frenzel K, et al. Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med. 2014; [Epub ahead of print] Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342–9. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52. Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001;106:255–8. O’Doherty U, Peng M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, et al. Human blood contains two subsets of dendritic cells, on immunologically mature and the other immature. Immunology. 1994;82:487–93. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol. 2004;5:1219–26. Blasius AL, Giursato E, Cella M, Schreiber RD, Shaw AS, Colonna M. Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naïve mouse, but a promiscuous cell surface antigen following IFN stimulation. J Immunol. 2006;177:3260–5. Blasius AL, Colonna M. Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H. Trends Immunol. 2006;27:255–60. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–9. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. BDCA-2, BDCA-3 and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165:6037–46. Huysamen C, Willment JA, Dennehy KM, Brown GD. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J Biol Chem. 2008;283:16693–701. Haniffa M, Shin A, Bigley V, McGovern N, Teo P, See P, et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 2012;37:60–73. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60. McKenna K, Beignon AS, Bhardwaj N. Plasmacytoid dendritic cells: linking innate and adaptive immunity. J Virol. 2005;79:17–27. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology. 2014;59:2034–42. Rigamonte E, Zordan P, Sciorati C, Rovere-Querini P, Brunelli S. Macrophage plasticity in skeletal muscle repair. Biomed Res Int. 2014;2014:560529. Gurtner GC, Werner S, Barrandon Y, Ferguson MW. Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Nature. 453:314-21. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341:738–46. Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mod Med. 2011;13:e23. Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. J Leukoc Biol. 2013;93:875–81. Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol. 2013;183:1352–563. Lech M, Anders HJ. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta. 1832;2013:989–97. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71–100. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati. : Macrophage plasticity and polarization in tissue repair and remodeling. J Pathol. 2013;229:176–85. Ospelt C, Gay S. TLRs and chronic inflammation. Int J Biochem Cell Biol. 2010;42:495–505. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11:373–84. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;12:677–86. Bryan N, Ahswin H, Smart N, Bayon Y, Wohlert S, Hunt JA. Reactive oxygen species (ROS) – a family of fate deciding molecules pivotal in constructive inflammation and wound healing. Eur Cell Mater. 2012;24:349–265. Reichner JS, Meszaros AJ, Louis CA, Henry Jr WL, Mastrofrancesco B, Martin BA, et al. Molecular and metabolic evidence for the restricted expression of nitric oxide synthase in healing wounds. Am J Pathol. 1999;154:1097–104. Horiguchi M, Ota M, Rifkin. Matrix control of transforming growth factor-β function. J Biochem. 2012;152:321–9. Doyle JJ, Gerber EE, Dietz HC. Matrix-dependent perturbation of TGF-β signaling and disease. FEBS Lett. 2012;586:2003–15. Butterfield TA, Best TM, Merrick MA. The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair. J Athl Train. 2006;41:457–65. Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol. 2000;165:435–41. Meszaros AJ, Reichner JS, Albina JE. Macrophage phagocytosis of wound neutrophils. J Leukoc Biol. 1999;65:35–42. El Kebir D, Filep JG. Targeting neutrophil apoptosis for enhancing the resolution of inflammation. Cells. 2013;2:330–48. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. 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;101:890–8. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest. 2002;109:41–50. Voll RE, Hermann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 390:350-51. Savill J. Apoptosis in resolution of inflammation. J Leukoc Biol. 1997;61:375–80. Korns D, Frasch SC, Fernandez-Boyanapalli R, Henson PM, Bratton DL. Modulation of macrophage efferocytosis in inflammation. Front Immunol. 2010;2:57. DiDonato JA, Mercurio F, Karin M. NF-κB and the link between inflammation and cancer. Immunol Rev. 2012;246:379–400. Wang Y, John R, Chen J, Richardson JA, Shelton JM, Bennett M, et al. IRF-1 promotes inflammation early after ischemic acute kidney injury. Nephrol. 2009;20:1544–55. Lassen S, Lech M, Römmele C, Mittruecker HW, Mak TW, Anders HJ. Ischemia reperfusion induces IFN regulatory factor 4 in renal dendritic cells, which suppresses postischemic inflammation and prevents acute renal failure. J Immunol. 2010;185:1976–83. Tamura T, Tailor P, Yamaoka K, Kong HJ, Tsujimura H, O’Shea JJ, et al. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol. 2005;174:2573–81. Brancato SK, Albina JE. Wound macrophages as key regulators of repair: origin, phenotype and function. Am J Pathol. 2011;178:19–25. Song E, Ouyang N, Hörbelt M, Antus B, Wang M, Exton MS. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol. 2000;204:19–28. 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. Khalil N, Bereznay O, Sporn M, Greenberg AH. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med. 1989;170:727–37. Vidal B, Serrano AL, Tjwa M, Suelves M, Ardite E, De Mori R, et al. Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev. 2008;22:1747–52. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 2009;e1000371. Wehner S, Buchholz BM, Schuchtrup S, Rocke A, Schaefer N, Lysson M, et al. Mechanical strain and TLR4 synergistically induce cell-specific inflammatory gene expression in intestinal smooth muscle cells and peritoneal macrophages. Am J Physiol Gastrointest Liver Physiol. 2010;299:G1187–97. Blakney AK, Swartzlander MD, Bryant SJ. The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J Biomed Mater Res A. 2012;100:1375–86. Galván-Peña S, O’Neill LA. Metabolic reprogramming in macrophage polarization. Front Immunol. 2014;5:420. Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther. 2013;15:215. Krieg T, Abraham D, Lafyatis R. Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res Ther. 2007;2:S4. Abraham DJ, Eckes B, Rajkumar V, Krieg T. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr Rheumatol Rep. 2007;9:136–43. Kirk TZ, Mark ME, Chua CC, Chua BH, Mayes MD. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem. 1995;270:3423–8. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16. Hinz B, Gabbiani G. Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives. F1000 Biol Rep. 2010;2:78. Hu B, Phan SH. Myofibroblasts. Curr Opin Rheumatol. 2012;25:71–7. Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmoulière A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180:1340–55. Beon M, Harley RA, Wessels A, Silver RM, Ludwicka-Bradley A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol. 2004;22:733–42. Watsky MA, Weber KT, Sun Y, Postlethwaite A. New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies. Int Rev Cell Mol Biol. 2010;282:165–92. Li J, Zu X, Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol. 2009;175:1380–8. Rieder F, Kessler SP, West GA, Bhilocha S, de la Motte C, Sadler TM, et al. Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am J Pathol. 2011;179:2660–73. Goumans M, van Zonneveld AJ, ten Dijke P. Transforming growth factor β-induced endothelial-to-mesenchymal transition: A switch to cardiac fibrosis? Trends Cardiovasc Med. 2008;19:293–8. Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. 2009;19:116–27. Van Meeteren LA, ten Dijke P. Regulation of endothelial cell plasticity by TGFβ. Cell Tissue Res. 2012;347:177–86. Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol. 2011;179:1074–80. Piera-Velazquez S, Jimenez SA. Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis Tissue Repair. 2012;5 Suppl 1:S7. Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol. 2013;2013:835948. Zordan P, Rigamonte E, Freudenberg K, Conti V, Azzoni E, Rovere-Querini P, et al. Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. Cell Death Dis. 2014;5:e1031. Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2. J Cell Physiol. 2013;228:1774–83. Robins SP, Milne G, Duncan A, Davies C, Butt R, Greiling D, et al. Increased skin collagen extractability and proportions of collagen type III are not normalized after 6 months healing of human excisional wounds. J Invest Dermatol. 2003;121:267–72. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Műller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184:3964–77. Rodero MP, Legrand JM, Bou-Gharios G, Khosrotehrani K. Wound-associated macrophages control collagen 1α2 transcription during the early stages of skin wound healing. Exp Dermatol. 2013;22:143–5. Desmoulière 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. Jun JI, Lau LF. Cellular senescence controls fibrosis in wound healing. Aging (Albany NY). 2010;2:627–31. Fivenson DP, Faria DT, Nickoloff BJ, Polverini PJ, Kunkel SL, Burdick M, et al. Chemokine and inflammatory cytokine changes during chronic wound healing. Wound Repair Regen. 1997;5:310–22. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, et al. CXC chemokines in angiogenesis. J Leukoc Biol. 2000;68:1–8. Crowther M, Brown NJ, Bishop ET, Lewis CE. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol. 2001;70:478–90. Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benvon RC, Duffield JS, 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;178:528–5295. Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrated the regression of murine liver fibrosis. Proc Natl Acad Sci USA. 2012;109:E3186–95. Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology. 2014;146:1339–50. Fiorucci S, Antonelli E, Distrutti E, Severino B, Fiorentina R, Baldoni M, et al. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation. Hepatology. 2004;39:365–75. Rullier A, Gillibert-Duplantier J, Costet P, Cubel G, Haurie V, Petibois C, et al. Proteinase-activated receptor 1 knockout reduces experimentally induced liver fibrosis. Am J Physiol Gastointest Liver Physiol. 2008;294:G226–35. Kallis YN, Scotton CJ, Mackinnon AC, Goldin RD, Wright NA, Iredale JP, et al. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages. PLoS One. 2014;9:e86241. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9. Ghosh AK, Quaggin SE, Vaughan DE. Molecular basis of organ fibrosis: potential therapeutic approaches. Exp Biol Med. 2013;238:461–81. White ES, Mantovani AR. Inflammation, wound repair and fibrosis: reassessing the spectrum of tissue injury and resolution. J Pathol. 2013;229:141–4. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14:181–94. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New Engl J Med. 2004;351:1296–305. Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain, 1950 to 2002. Lancet. 2006;367:52–6. Lev B, Collar HR, King Jr TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183:431–40. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165–70. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–67. Rosenbloom J, Castro SV, Jimenez SA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. 2010;152:159–66. Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;8:42–54. Fleming JN, Schwartz SM. The pathology of scleroderma vascular disease. Rheum Dis Clin North Am. 2008;34:41–55. Farkas L, Kolb M. Pulmonary microcirculation in interstitial lung disease. Proc Am Thorac Soc. 2011;8:516–21. Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65:1953–62. Rongvaux A, Willinger T, Martinek J, Strowik T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32:364–72. Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, et al. The immunology of fibrosis. Annu Rev Immunol. 2013;131:977–93. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Sem Liver Dis. 2010;30:245–57. Karlmark KR, Tacke F, Dunay IR. Monocytes in health and disease – Minireview. Eur J Microbiol Immunol (Bp). 2012;2:97–102. Rafii R, Juarez MM, Albertson TE, Chan AL. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis. 2013;5:48–73. Meng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol. 2014;10:493–503. Stramer BM, Mori R, Martin P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J invest Dermatol. 2007;127:1009–17. Shen B, Liu X, Fan Y, Qiu J. Macrophages regulate renal fibrosis through modulating TGFβ superfamily signaling. Inflammation. 2014;[Epub ahead of print]. Kossakowska AE, Edwards DR, Lee SS, Urbanski LS, Stabbler AL, Zhang CL, et al. Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J Pathol. 1998;153:1895–902. Manoury B, Nénan S, Guénon I, LAgente V, Boichot E. Influence of early neutrophil depletion on MMPs/TIMP-1 balance in bleomycin-induced lung fibrosis. Int Immunopharmacol. 2007;7:900–11. Sedrakyan S, Da Sacco S, Milanesi A, Petrosyan A, Varimezova R, Warburton D, et al. Injection of amniotic fluid stem cells delays progression of renal fibrosis. J Am Soc Nephrol. 2012;23:661–73. Swenson-Fields KI, Vivian CJ, Salah SM, Peda JD, Davis BM, van Rooijen N, et al. Macrophages promote polycystic kidney disease progression. Kidney Int. 2013;83:855-64 Belliere J, Casemayou A, Ducasse L, Zakaroff-Girard A, Martins F, Iacovoni JS, et al. Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury. J Am Soc Nephrol. 2014; [Epub ahead of print] Sutton TA, Hato T, Mai E, Yoshimoto M, Kuehl S, Anderson M, et al. P53 is renoprotective after ischemic kidney injury by reducing inflammation. J Am Soc Nephrol. 2013;24:113–24. Madsen DH, Bugge TH. Imaging collagen degradation in vivo highlights a key role for M2-polarized macrophages in extracellular matrix degradation. Oncoimmunology. 2013;2:e27127. Madsen DH, Leonard D, Masedunskas A, Moyer A, Jürgensen HJ, Peters DE, et al. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol. 2013;202:951–66. Zheng D, Wang Y, Cao Q, Lee VW, Zheng G, Sun Y, et al. Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus. Nephron Exp Nephrol. 2011;118:e87–99. Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L, Chang DH, et al. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int. 2007;72:290–9. Kushiyama T, Oda T, Yamada M, Higashi K, Yamamoto K, Sakurai Y, et al. Alteration in the phenotype of macrophages in the repair of renal interstitial fibrosis in mice. Nephrology (Carlton). 2011;16:522–35. Dreymueller D, Denecke B, Ludwig A, Jahnen-Dechent W. Embryonic stem cell-derived M2-like macrophages delay cutaneous wound healing. Wound Repair Regen. 2013;21:44–54. Heymann F, Hammerich L, Storch D, Bartneck M, Huss S, Rűsseler V, et al. Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice. Hepatology. 2012;55:898-909 Trujillo G, O’Connor EC, Kunkel SL, Hogaboam CM. A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2008;172:1209–21. Locatelli I, Sutti S, Jindal A, Vacchiano M, Bozzola C, Reutelingsperger C, et al. Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice. Hepatology. 2014;60:531–44. Misson P, van den Brűle S, Barbarin V, Lison D, Huaux F. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004;76:926–32. Guilherme RF, Xisto DG, Kunkel SL, Freire-de-Lima CG, Rocco PR, Neves JS, et al. Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A (4) synthetic analog. Am J Respir Cell Mol Biol. 2013;49:1029–37. Wijesundera KK, Izawa T, Tennakoon AH, Murakami H, Golbar HM, Katou-Ichikawa C, et al. M1- and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide (TAA), focusing on Iba1 and galectin-3. Exp Mol Pathol. 2014;96:382–92. Wijesundera KK, Izawa T, Murakami H, Tennakoon AH, Golbar HM, Kato-Ichikawa C, et al. M1- and M2-macrophage polarization in thioacetamide (TAA)-induced rat liver lesions: a possible analysis for hepato-pathology. Histol Histopathol. 2014;29:497–511. O’Reilly S. Innate immunity in systemic sclerosis pathogenesis. Clin Sci (Lond). 2014;126:329–37. Wermuth PJ, Del Galdo F, Jimenez SA. Induction of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents. Arthritis Rheum. 2009;60:1508–18. Del Galdo F, Wermuth PJ, Addya S, Fortina P, Jimenez SA. NFκB activation and stimulation of chemokine production in normal human macrophages by gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis. Ann Rheum Dis. 2010;69:2024–33. Schmidt-Lauber C, Bossaller L, Abujudeh HH, Vladimer GI, Christ A, Fitzgerald KA, et al. Gadolinium-based compounds induce NLRP3-dependent IL-1B production and peritoneal inflammation. Ann Rheum Dis. 2014; [Epub ahead of print]. Farina GA, York MR, Di Marzio M, Collins CA, Meller S, Homey B, et al. Poly(I:C) drives type I IFN- and TGFβ-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol. 2010;130:2583–93. Agarwal SK, Wu M, Livingston CK, Parks DH, Mayes MD, Arnett FC, et al. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Ther. 2011;13:R3. Farina A, Cirone M, York M, Lenna S, Padilla C, McLaughlin S, et al. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol. 2014;134:954–64. Stifano G, Affandi AJ, Mathes AL, Rice LM, Nakerakanti S, Nazari B, et al. Chronic Toll-like receptor 4 stimulation in skin induces inflammation, macrophage activation, transforming growth factor beta signature gene expression, and fibrosis. Arthritis Res Ther. 2014;16:R136. Braga TT, Correa-Costa-M, Guise YF, Castoldi A, de Oliveira CD, Hyane MI, et al. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages. Mol Med. 2012;18:1231-39 Hanke ML, Angle A, Kielian T. MyD88-dependent signaling influences fibrosis and alternative macrophage activation during Staphylococcus aureus biofilm infection. PLoS One. 2012;7:e42476. Dessing MC, Tammaro A, Pulskens WP, Teske GJ, Butter LM, Claessen N, et al. The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion. Kidney Int. 2014; [Epub ahead of print]. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989–2003. Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. 2004;26:13–24. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;28:509–37. Ritter M, Buechler C, Langmann T, Schmitz G. Genomic organization and chromosomal localization of the human CD163 (M13) gene: a member of the scavenger receptor cysteine-rich superfamily. Biochem Biophys Res Commun. 1999;260:466–74. 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. Nakayama W, Jinnin M, Makino K, Kajhara I, Makino T, Fukushima S, et al. Serum levels of soluble CD163 in patients with systemic sclerosis. Rheumatol Int. 2012;32:403–7. Shimizu K, Ogawa F, Yoshizaki A, Akiyama Y, Kuwatsuka Y, Okazaki S, et al. Increased serum levels of soluble CD163 in patients with scleroderma. Clin Rheumatol. 2012;31:1059–64. Kowal-Bielecka O, Bielecki M, Guiducci S, Trzcinska-Butkiewicz B, Michalska-Jakubus M, Matucci-Cerinic M, 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. Higashi-Kuwata N, Jinnin M, Makino T, Fukushima S, Inoue Y, Muchemwa FC, 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. Etzerodt A, Maniecki MB, Møller K, Møller HJ, Moestrup SK. Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163. J Leukoc Biol. 2010;88:1201–5. Bohgaki T, Amasaki Y, Nishimura N, Bohgaki M, Yamashita Y, Nishio M, et al. Upregulated expression of tumour necrosis factor {alpha} converting enzyme in peripheral monocytes of patients with early systemic sclerosis. Ann Rheum Dis. 2005;64:1165–73. Carulli MT, Ong VH, Ponticos M, Shiwen X, Abraham DJ, Black CM, et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum. 2005;52:3772–82. Mathes AL, Christmann RB, Stifano G, Affandi AJ, Radstake TR, Farina GA, 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. Mathai SK, Gulati M, Peng X, Russell TR, Shaw AC, Rubinowitz AN, et al. Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab Invest. 2010;90:812–23. Christmann RB, Sampaio-Barros P, Stifano G, Borges CL, de Varvalho CR, Kairalla R, et al. Association of interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 2014;66:714–25. Leach HG, Chrobak I, Han R, Trojanowska M. Endothelial cells recruit macrophages and contribute to a fibrotic milieu in bleomycin lung injury. Am J Respir Cell Mol Biol. 2013;49:1093–101. Stawski L, Haines P, Fine A, Rudnicka L, Trojanowska M. MMP-12 deficiency attenuates angiotensin II-induced vascular injury, M2 macrophage accumulation, and skin and heart fibrosis. PLoS One. 2014;9:e109763. Nestle FO, Zheng XG, Thompson CB, Turka LA, Nickoloff BJ. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol. 1993;151:6535–45. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9:679–91. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boynam O, et al. Plasmcytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med. 2005;202:135–43. Tamoutounour S, Guilliams M, Montanana Sanchis F, Liu H, Terhorst D, Malosse C, et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity. 2013;39:925–38. Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol. 2014;14:417–28. Aiba S, Tabata N, Ohtani H, Tagami H. CD34+ spindle-shaped cells selectively disappear from the skin lesion of scleroderma. Arch Dermatol. 130:593-97. de-Sa-Earp AP, do Nascimento AP, Carniero SC, Porto LC, Monte-Alto-Costa A. Dermal dendritic cell population and blood vessels are diminished in the skin of systemic sclerosis patients: relationship with fibrosis degree and disease duration. Am J Dermatopathol. 2013;35:438-44. van Bon L, Popa C, Huijbens R, Vonk M, York M, Simms R, et al. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2010;69:1539–47. Tan FK, Zhou X, Mayes MD, Gourh P, Guo X, Marcum C, et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology. 2006;45:694–702. Lu TT. Dendritic cells: novel players in fibrosis and scleroderma. Curr Rheumatol Rep. 2012;14:30–8. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000–1. Jimenez SA, Artlett CM, Sandorfi N, Derk C, Latinis K, Sawaya H, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum. 2004;50:2660–6. Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum. 2006;35:238–49. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Path. 2014;9:157–79. Ryu JH, Moua T, Daniels CD, Hartman TE, Yi ES, Utz JP, et al. Idiopathic pulmonary fibrosis: evolving concepts. Mayo Clin Proc. 2014;89:1130–42. Ji WJ, Ma YQ, Zhou X, Zhang YD, Lu RY, Sun HY, et al. Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin-induced pulmonary injury. J Immunol Methods. 2014;403:7–16. Ji WJ, Ma YQ, Zhang YD, Lu RY, Guo ZZ, Hu DC, et al. Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments. PLoS One. 2013;8:e81090. Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT, et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med. 2011;184:569–81. Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP, et al. Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum. 2008;58:2854–65. Del Galdo F, Lisanti MP, Jimenez SA. Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 2008;20:713–9. Tourkina E, Richard M, Gööz P, Bonner M, Pannu J, Harley R, et al. Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol. 2008;294:L843–61. Reese C, Perry B, Heywood J, Bonner M, Visconti RP, Lee R, et al. Caveolin-1 deficiency may predispose African Americans to systemic sclerosis-related interstitial lung disease. Arthritis Rheumatol. 2014;66:1909–19. Tourkina E, Bonner M, Oates J, Hofbauer A, Richard M, Znoyko S, et al. Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide. Fibrogenesis Tissue Repair. 2011;4:15. Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol. 2014; [Epub ahead of print] Illman SA, Lohi J, Keski-Oja J. Epilysin (MMP28)—structure, expression and potential functions. Exp Dermatol. 2008;17:897–907. Gan Y, Herzog EL. MMP28 and macrophage polarization: orchestrating the attack of the mac. J Leukoc Biol. 2014;95:1–3. Gharib SA, Johnston LK, Huizar I, Birkland TP, Hanson J, Wang Y, et al. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol. 2014;95:9–18. Arras M, Huaux F, Vink A, Delos M, Coutelier JP, Many MC, et al. Interleukin-9 reduces lung fibrosis and type 2 immune polarization induced by silica particles in a murine model. Am J Respir Cell Mol Biol. 2001;24:368–75. Sun L, Louie MC, Vannella KM, Wilke CA, LeVine AM, Moore BB, et al. New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis. Am J Physiol Lung Cell Mol Physiol. 2011;300:L341–53. Tao B, Jin W, Xu J, Liang Z, Yao J, Zhang Y, et al. Myeloid-specific disruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposes mice to pulmonary fibrosis. J Immunol. 2014;193:2801–11. Stahl M, Schupp J, Jäger B, Schmid M, Zissel G, Müller-Zuernheim J, et al. Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation. PLoS One. 2013;8:e81382. Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Kambouchner M, Valeyre D, Crestani B, et al. Dendritic cells accumulate in human fibrotic interstitial lung disease. Am J Respir Crit Care Med. 2007;176:1007–14. Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Valeyre D, Soumelis V, Crestani B, et al. Cutting edge: nonproliferating mature immune cells form a novel type of organized lymphoid structure in idiopathic pulmonary fibrosis. J Immunol. 2006;176:5735–9. Bantsimba-Malanda C, Marchal-Somme J, Goven D, Freynet O, Michel L, Crestani B, et al. A role for dendritic cells in bleomycin-induced pulmonary fibrosis in mice? Am J Respir Crit Care Med. 2010;182:385–95. Ballater R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18. Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog. 2014;10:e1004032. Zhu J, Xu Z, Chan S, Zhou S, Zhang W, Chi Y, et al. Parasitic antigens alter macrophage polarization during Schistosome japonicum infection in mice. Parasit Vectors. 2014;7:122. Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, et al. Functional contribution of eleveated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One. 2010;5:e11049. Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z, et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology. 2013;57:385–98. Ansari AW, Schmidt RE, Shankare EM, Kamarulzaman A. Immuno-pathomechanism of liver fibrosis: targeting chemokine CCL2-mediated HIV:HCV nexus. J Trans Med. 2014;12:341. Tacke F. Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. Fibrogenesis Tissue Repair. 2012;6(Suppl1):S27. Zimmermann HW, Trautwein C, Tacke F. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. Front Physiol. 2012;3:56. Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Mockel D, et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut. 2014;63:1960–71. Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatits through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1310–21. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology. 2009;50:261–74. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50:185–97. Baeck C, Wehr A, Karlmarck KR, Heymann F, Vucur M, Gassler N, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61:416–26. Baeck C, Wei X, Bartneck M, Fech V, Heymann F, Gassler N, et al. Pharmacological inhibition of the chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology. 2014;59:1060–72. Karlmark KR, Zimmermann HW, Roderburg C, Gassler N, Wasmuth HE, Luedde T, et al. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology. 2010;52:1769–82. Zimmermann HW, Tacke F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets. 2011;10:509–36. Connolly MK, Bedrosian AS, Mallen-St Clair J, Mitchell AP, Ibrahim J, Stroud A, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest. 2009;119:3213–25. Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Yamada T, Imai N, et al. Identification of alternatively activated macrophages in new-onset-paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion. Histopathology. 2011;58:198–210. Glim JE, Niessen FB, Everts V, van Egmond M, Beelen RHJ. Platelet derived growth factor-CC secreted by M2 macrophages induces alpha-smooth muscle actin expression by dermal and gingival fibroblasts. Immunobiology. 2013;218:924–9. Toki D, Zhang W, Hor KL, Liuwantara D, Alexander SI, Yi Z, et al. The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. Am J Transplant. 2014;14:2126–36. Dong X, Bachman LA, Miller MN, Nath KA, Griffin MD. Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction. Kidney Int. 2008;74:1294–309. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–74. Wang L, Li YL, Zhang CC, Cui W, Wang X, Xia Y, et al. Inhibition of toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation. Cardiovasc Res. 2014;101:383–92. Ma Y, Halade GV, Zhang J, Ramirez TA, Levin D, Voorhees A, et al. Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res. 2013;112:675–88. Shivshankar P, Halade GV, Calhoun C, Escobar GP, Mehr AJ, Jimenez F, et al. Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation in mice after myocardial infarction. J Mol Cell Cardiol. 2014;76C:84–93. Serrano AL, Mann CJ, Vidal B, Ardite E, Perdiguero E, Munoz-Canoves P. Cellular and molecular mechanisms regulating fibrosis in skeletal muscle repair and disease. Curr Top Dev Biol. 2011;96:167–201. Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into anti-inflammatory macrophages to support myogenesis. J Exp Med. 2007;204:1057–69. Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, et al. A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci USA. 2009;106:17475–80. Villalta SA, Nguyen HX, Deng B, Gotoh T, Tidball JG. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet. 2009;18:482–96. Wehling-Henricks M, Jordan MC, Gotoh T, Grody WW, Roos KP, Tidball JH. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PLoS One. 2010;5:e10763. Zhang L, Dong Y, Dong Y, Cheng J, Du J. Role of integrin-β3 protein in macrophage polarization and regeneration of injured muscle. J Biol Chem. 2012;287:6177–86. Molumdar K, Liang F, Giordano C, Lemaire C, Okazaki T, Bourdon J, et al. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2. EMBO Mol Med. 2014;6:1476–92. Percival JM, Whitehead NP, Adams ME, Adama CM, Neavo JA, Froehner SC. Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol. 2012;228:77–87. Huang P, Zhao XS, Fields M, Ransohoff RM, Zhou L. Imatinib attenuates skeletal muscle dystrophy in mdx mice. FASEB J. 2009;23:2539–48. Ito T, Ogawa R, Uezumi A, Ohtani T, Watanabe Y, Tsujikawa K, et al. Imatinib attennuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors. Neuromuscul Disord. 2013;23:346–56. Mantovani A, Vecchi A, Allavena P. Pharmacological modulation of monocytes and macrophages. Curr Opin Pharmacol. 2014;17C:38–44. Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007;117:902–9. Venbervliet B, Homey B, Durand I, Massacrier C, Aїt-Yahia S, de Boutellier O, et al. Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial sites. Eur J Immunol. 2002;32:231–42. Ben-Mordechai T, Holbova R, Landa-Rouben N, Harel-Adar T, Feinberg MS, Abd Elrahman I, et al. Macrophage subpopulations are essential for infarct repair with and without stem cell therapy. J Am Coll Cardiol. 2013;62:1890–901. Avraham-Davidi I, Yona S, Grunewald M, Landsman L, Cochain C, Silvestre JS, et al. On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells. J Exp Med. 2013;210:2611–25. Cao Q, Wang Y, Zheng D, Sun Y, Wang C, Wang XM, et al. Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotypic switch in vivo. Kidney Int. 2014;85:794–806. Agrawal A, Manchester M. Differential uptake of chemically modified cowpea mosaic virus nanoparticles in macrophage subpopulations present in inflammatory and tumor microenvironments. Biomacromolecules. 2012;13:3320–6. Al Faraj A, Shaik AS, Afzal S, Al Sayed B, Halwani R. MR imaging and targeting of a specific alveolar macrophage subpopulation in LPS-induced COPD animal model using antibody-conjugated magnetic nanoparticles. Int J Nanomedicine. 2014;9:1491–503. Movahedi K, Schoonooghe S, Laoui D, Houbracken I, Waelput W, Breckpot K, et al. Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor associated macrophages. Cancer Res. 2012;72:4165–77. Ellerby HM, Arap W, Ellerby LM, Kain R, Andrusiak R, Rio GD, et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med. 1999;5:1032–8. Cieslewicz M, Tang J, Yu JL, Cao H, Zavajevski M, Motoyama K, et al. Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. Proc Natl Acad Sci USA. 2013;110:15919–24.