Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis

Journal of Innate Immunity

Volumn 4, Issue 5-6, 2012, Pages 463-477

  Weidenbusch, Marc ^a   Anders, Hans Joachim ^a  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

Ischemia; Leukocytes; Pathology; Polarization; Toll like receptors; Wound healing

Indexed keywords

CYTOKINE; GROWTH FACTOR; INFLAMMASOME; PROTEINASE; TOLL LIKE RECEPTOR;

APOPTOSIS; CELL POLARITY; EXTRACELLULAR MATRIX; FIBROSIS; HOMEOSTASIS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; INFLAMMATION; MACROPHAGE; NONHUMAN; PARENCHYMA; PHENOTYPE; PRIORITY JOURNAL; REVIEW; STROMA; TISSUE INJURY; TUMOR GROWTH; TUMOR MICROENVIRONMENT; WOUND HEALING;

CELLULAR MICROENVIRONMENT; FIBROSIS; HOMEOSTASIS; HUMANS; INFLAMMATION; MACROPHAGES; ORGAN SPECIFICITY; PHENOTYPE; WOUND HEALING;

EID: 84866036082     PISSN: 1662811X     EISSN: 16628128     Source Type: Journal    
DOI: 10.1159/000336717     Document Type: Review

References (180)

1. 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; 25: 677-686. (Pubitemid 39457982)
2. Mosser DM, Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958-969.
3. Gordon S, Taylor PR: Monocyte and macro-phage heterogeneity. Nat Rev Immunol 2005; 5: 953-964.
4. Medzhitov R: Origin and physiological roles of inflammation. Nature 2008; 454:428-435.
5. Matzinger P: Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007; 8:11-13. (Pubitemid 46242350)
6. Matzinger P, Kamala T: Tissue-based class control: the other side of tolerance. Nat Rev Immunol 2011; 11: 221-230.
7. MacDonald TT, Monteleone I, Fantini MC, Monteleone G: Regulation of homeostasis and inflammation in the intestine. Gastro-enterology 2011; 140:1768-1775.
8. Messier-Solek C, Buckley KM, Rast JP: Highly diversified innate receptor systems and new forms of animal immunity. Semin Immunol 2010; 22: 39-47.
9. Rast JP, Smith LC, Loza-Coll M, Hibino T, Litman GW: Genomic insights into the immune system of the sea urchin. Science 2006; 314: 952-956. (Pubitemid 44749931)
10. Kapsenberg ML: Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003; 3:984-993. (Pubitemid 37521540)
11. Stefater JA 3rd, Ren S, Lang RA, Duffield JS: Metchnikoff's policemen: macrophages in development, homeostasis and regeneration. Trends Mol Med 2011; 17:743-752.
12. Chorro L, Geissmann F: Development and homeostasis of 'resident' myeloid cells: the case of the Langerhans cell. Trends Immunol 2010; 31:438-445.
13. Gurtner GC, Werner S, Barrandon Y, Long-aker MT: Wound repair and regeneration. Nature 2008; 453: 314-321. (Pubitemid 351693137)
14. Bonventre JV, Yang L: Cellular pathophysiol-ogy of ischemic acute kidney injury. J Clin Invest 2011; 121:4210-4221.
15. Semple JW, Italiano JE Jr, Freedman J: Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
16. Galli SJ, Borregaard N, Wynn TA: Phenotyp-ic and functional plasticity of cells of innate immunity: macrophages, mast cells and neu-trophils. Nat Immunol 2011; 12:1035-1044.
17. Rock KL, Latz E, Ontiveros F, Kono H: The sterile inflammatory response. Annu Rev Immunol 2010; 28:321-342.
18. Rakoff-Nahoum S, Paglino J, Eslami-Var-zaneh F, Edberg S, Medzhitov R: Recognition of commensal microflora by toll-like receptors is required for intestinal homeosta-sis. Cell 2004; 118:229-241. (Pubitemid 38962578)
19. Lee SB, Kalluri R: Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl 2010; 119:S22-S26.
20. Anders HJ, Ryu M: Renal microenviron-ments and macrophage phenotypes determine progression or resolution of renal inf lammation and fibrosis. Kidney Int 2011; 80: 915-925.
21. Singer AJ, Clark RA: Cutaneous wound healing. N Engl J Med 1999; 341: 738-746. (Pubitemid 29407375)
22. Martin P, Leibovich SJ: Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 2005; 15: 599-607. (Pubitemid 41619424)
23. Drake TA, Cheng J, Chang A, Taylor FB Jr: Expression of tissue factor, thrombomodu-lin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993; 142: 1458-1470. (Pubitemid 24058133)
24. Meisel SR, Xu X P, Edgington TS, Cercek B, Ong J, Kaul S, Shah PK: Dose-dependent modulation of tissue factor protein and pro-coagulant activity in human monocyte-de-rived macrophages by oxidized low density lipoprotein. J Atheroscler Thromb 2011; 18: 596-603.
25. Chow A, Brown BD, Merad M: Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 2011; 11:788-798.
26. Kawai T, Akira S: Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34: 637-650.
27. Patole PS, Schubert S, Hildinger K, Khandoga S, Khandoga A, Segerer S, Henger A, Kretzler M, Werner M, Krombach F, Schlondorff D, Anders HJ: Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney Int 2005; 68:2582-2587. (Pubitemid 43251003)
28. Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820.
29. Lech M, Avila-Ferrufino A, Skuginna V, Susanti HE, Anders HJ: Quantitative expression of rig-like helicase, nod-like receptor and inflammasome-related mRNAs in humans and mice. Int Immunol 2010; 22: 717-728.
30. Rock KL, Lai JJ, Kono H: Innate and adaptive immune responses to cell death. Immunol Rev 2011; 243: 191-205.
31. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA: IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 2011; 12: 231-238.
32. Sorokin L: The impact of the extracellular matrix on inflammation. Nat Rev Immunol 2010; 10: 712-723.
33. Swaminathan S, Griffin MD: First responders: understanding monocyte-lineage traffic in the acutely injured kidney. Kidney Int 2008; 74: 1509-1511.
34. Cowin AJ, Brosnan MP, Holmes TM, Ferguson MW: Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Dev Dyn 1998; 212:385-393. (Pubitemid 28294867)
35. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, Roers A, Eming SA: Differential roles of macrophages in diverse phases of skin repair. J Immunol 2010; 184: 3964-3977.
36. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, Hainzl A, Schatz S, Qi Y, Schlecht A, Weiss JM, Wlaschek M, Sunderkotter C, Scharffetter-Kochanek K: An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 2011; 121:985-997.
37. Anders HJ: Toll-like receptors and danger signaling in kidney injury. J Am Soc Nephrol 2010; 21: 1270-1274.
38. Benoit M, Desnues B, Mege JL: Macrophage polarization in bacterial infections. J Immunol 2008; 181: 3733-3739.
39. Kono H, Rock KL: How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8: 279-289. (Pubitemid 351432799)
40. Ikezumi Y, Atkins RC, Nikolic-Paterson DJ: Interferon-gamma augments acute macro-phage-mediated renal injury via a glucocorticoid-sensitive mechanism. J Am Soc Nephrol 2003; 14:888-898. (Pubitemid 36359271)
41. Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Perez de Lema G, Strutz F, Bauer S, Rutz M, Wagner H, Grone HJ, Schlondorff D: Activation of toll-like recep-tor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 2004; 18: 534-536.
42. Allam R, Pawar RD, Kulkarni OP, Hornung V, Hartmann G, Segerer S, Akira S, Endres S, Anders HJ: Viral 5'-triphosphate RNA and non-CpG DNA aggravate autoimmunity and lupus nephritis via distinct TLR-inde-pendent immune responses. Eur J Immunol 2008; 38: 3487-3498.
43. Patole PS, Grone HJ, Segerer S, Ciubar R, Belemezova E, Henger A, Kretzler M, Schlondorff D, Anders HJ: Viral double-stranded RNA aggravates lupus nephritis through toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol 2005; 16: 1326-1338. (Pubitemid 41716517)
44. Patole PS, Pawar RD, Lichtnekert J, Lech M, Kulkarni OP, Ramanjaneyulu A, Segerer S, Anders HJ: Coactivation of toll-like recep-tor-3 and-7 in immune complex glomerulonephritis. J Autoimmun 2007; 29:52-59. (Pubitemid 47016916)
45. Pawar RD, Patole PS, Ellwart A, Lech M, Segerer S, Schlondorff D, Anders HJ: Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis. J Am Soc Nephrol 2006; 17:3365-3373. (Pubitemid 44865279)
46. Pawar RD, Patole PS, Zecher D, Segerer S, Kretzler M, Schlondorff D, Anders HJ: Tolllike receptor-7 modulates immune complex glomerulonephritis. J Am Soc Nephrol 2006; 17:141-149.
47. Anders HJ, Banas B, Linde Y, Weller L, Cohen CD, Kretzler M, Martin S, Vielhauer V, Schlondorff D, Grone HJ: Bacterial CpG-DNA aggravates immune complex glomeru-lonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J Am Soc Nephrol 2003; 14:317-326. (Pubitemid 36150855)
48. Jose MD, Ikezumi Y, van Rooijen N, Atkins RC, Chadban SJ: Macrophages act as effectors of tissue damage in acute renal allograft rejection. Transplantation 2003; 76: 1015-1022. (Pubitemid 37280827)
49. Bonventre J V, Zuk A: Ischemic acute renal failure: an inflammatory disease? Kidney Int 2004; 66:480-485. (Pubitemid 38981982)
50. Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, Ruhrberg C, Cantley LG: Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 2011; 22:317-326.
51. Lech M, Avila-Ferrufino A, Allam R, Segerer S, Khandoga A, Krombach F, Garlanda C, Mantovani A, Anders HJ: Resident dendritic cells prevent postischemic acute renal failure by help of single Ig I L-1 receptor-related protein. J Immunol 2009; 183: 4109-4118.
52. Wang Y, Cao Q, Zheng G, Lee VW, Zheng D, Li X, Tan TK, Harris DC: By homing to the kidney, activated macrophages potently exacerbate renal injury. Am J Pathol 2008; 172: 1491-1499. (Pubitemid 351793343)
53. Wang Y, Harris DC: Macrophages in renal disease. J Am Soc Nephrol 2011; 22:21-27.
54. Kulkarni O, Eulberg D, Selve N, Zollner S, Allam R, Pawar RD, Pfeiffer S, Segerer S, Klussmann S, Anders HJ: Anti-Ccl2 Spiegel-mer permits 75% dose reduction of cyclo-phosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice. J Pharmacol Exp Ther 2009; 328:371-377.
55. Kulkarni O, Pawar RD, Purschke W, Eulberg D, Selve N, Buchner K, Ninichuk V, Segerer S, Vielhauer V, Klussmann S, Anders HJ: Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J Am Soc Nephrol 2007; 18: 2350-2358. (Pubitemid 47203851)
56. King IL, Dickendesher TL, Segal BM: Circulating Ly-6c+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 2009; 113: 3190-3197.
57. Mildner A, Mack M, Schmidt H, Bruck W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M: CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the centra l nervous system. Brain 2009; 132: 2487-2500.
58. Smith PD, Smythies LE, Shen R, Greenwell-Wild T, Gliozzi M, Wahl SM: Intestinal mac-rophages and response to microbial encroachment. Mucosal Immunol 2011; 4:31-42.
59. Mowat AM, Bain CC: Mucosal macrophages in intestinal homeostasis and inflammation. J Innate Immun 2011; 3:550-564.
60. Allen JE, Wynn TA: Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 2011; 7:e1002003.
61. Oliphant CJ, Barlow JL, McKenzie AN: Insights into the initiation of type 2 immune responses. Immunology 2011; 134: 378-385.
62. Martinez FO, Helming L, Gordon S: Alternative activation of macrophages: an immu-nologic functional perspective. Annu Rev Immunol 2009; 27:451-483.
63. Savill J, Gregory C, Haslett C: Cell biology: eat me or die. Science 2003; 302: 1516-1517.
64. Savill J: Apoptosis in resolution of inflammation. J Leukoc Biol 1997; 61: 375-380. (Pubitemid 27219829)
65. Lucas M, Stuart LM, Savill J, Lacy-Hulbert A: Apoptotic cells and innate immune stimuli combine to regulate macrophage cyto-k ine secretion. J Immunol 2003; 171: 2610-2615. (Pubitemid 37025573)
66. Duffield JS: Macrophages and immunologic inflammation of the kidney. Semin Nephrol 2010; 30:234-254.
67. Liu G, Ma H, Qiu L, Li L, Cao Y, Ma J, Zhao Y: Phenotypic and functional switch of macrophages induced by regulatory CD4+CD25+ T cells in mice. Immunol Cell Biol 2010; 89: 130-142.
68. Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K: Negative regulation of toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci USA 2005; 102:15989-15994. (Pubitemid 41552855)
69. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Mat-suyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S: The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 2010; 11: 936-944.
70. El Chartouni C, Schwarzfischer L, Rehli M: Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming. Immuno-biolog y 2010; 215: 821-825.
71. Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, Carson WF, Cavassani KA, Li X, Lukacs NW, Hogaboam CM, Dou Y, Kunkel SL: Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 2009; 114:3244-3254.
72. Cao Q, Wang Y, Zheng D, Sun Y, Lee VW, Zheng G, Tan TK, Ince J, Alexander SI, Harris DC: IL-10/TGF-beta-modified macro-phages induce regulatory T cells and protect against adriamycin nephrosis. J Am Soc Nephrol 2010; 21: 933-942.
73. Kluth DC, Ainslie CV, Pearce WP, Finlay S, Clarke D, Anegon I, Rees AJ: Macrophages transfected with adenovirus to express IL-4 reduce inflammation in experimental glo-merulonephritis. J Immunol 2001; 166:4728-4736. (Pubitemid 32233761)
74. Wang Y, Wang YP, Zheng G, Lee VW, Ouy-ang L, Chang DH, Mahajan D, Coombs J, Wang YM, Alexander SI, Harris DC: Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 2007; 72:290-299. (Pubitemid 47172367)
75. Zheng D, Wang Y, Cao Q, Lee VW, Zheng G, Sun Y, Tan TK, Alexander SI, Harris DC: Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mel-litus. Nephron Exp Nephrol 2011; 118: e87-e99.
76. Barczyk K, Ehrchen J, Tenbrock K, Ahlmann M, Kneidl J, Viemann D, Roth J: Glucocorti-coids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3. Blood 2010; 116:446-455.
77. Bertalan R, Patocs A, Vasarhelyi B, Treszl A, Varga I, Szabo E, Tamas J, Toke J, Boyle B, Nobilis A, Rigo J Jr, Racz K: Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene. J Steroid Biochem Mol Biol 2008; 111:91-94.
78. Mirza R, Di Pietro LA, Koh TJ: Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol 2009; 175:2454-2462.
79. Morimoto H, Takahashi M, Shiba Y, Izawa A, Ise H, Hongo M, Hatake K, Motoyoshi K, Ikeda U: Bone marrow-derived CXCR4+ cells mobilized by macrophage colony-stimulating factor participate in the reduction of infarct area and improvement of cardiac remodeling after myocardial infarction in mice. Am J Pathol 2007; 171:755-766. (Pubitemid 47440975)
80. Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, DosReis GA: Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low) IL-10(high) regulatory phenotype in macro-phages. J Immunol 2010; 185: 2044-2050.
81. Lassen S, Lech M, Rommele C, Mittruecker HW, Mak TW, Anders HJ: Ischemia reperfu-sion induces IFN regulatory factor 4 in renal dendritic cells, which suppresses postische-mic inflammation and prevents acute renal failure. J Immunol 2010; 185: 1976-1983.
82. Huang XR, Kitching AR, Tipping PG, Hold-sworth SR: Interleukin-10 inhibits macro-phage-induced glomerular injury. J Am Soc Nephrol 2000; 11: 262-269. (Pubitemid 30064849)
83. Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Kawachi H, Nikolic-Paterson DJ, Uchi-yama M: Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat thy-1 mesangial proliferative glomerulonephritis. Am J Nephrol 2010; 31:273-282.
84. Ghielli M, Verstrepen WA, Nouwen EJ, De Broe ME: Inflammatory cells in renal regeneration. Ren Fail 1996; 18: 355-375. (Pubitemid 26240161)
85. Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, Gherardi RK, Chazaud B: Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 2007; 204:1057-1069. (Pubitemid 46798150)
86. Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M: Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 2009; 6:e1000113.
87. Shi J, Aisaki K, Ikawa Y, Wake K: Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 1998; 153: 515-525. (Pubitemid 28373662)
88. Ren F, Duan Z, Cheng Q, Shen X, Gao F, Bai L, Liu J, Busuttil RW, Kupiec-Weglinski JW, Zhai Y: Inhibition of glycogen synthase ki-nase 3 beta ameliorates liver ischemia reper-fusion injury by way of an interleukin-10- mediated immune regulatory mechanism. Hepatology 2011; 54:687-696.
89. Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H, Claussen B, Forster I, Brombacher F: Alternative macro-phage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 2004; 20: 623-635. (Pubitemid 38659504)
90. Barron L, Wynn TA: Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. Eur J Immunol 2011; 41: 2509-2514.
91. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV: Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 2010; 16: 535-543.
92. Quan TE, Cowper SE, Bucala R: The role of circulating fibrocytes in fibrosis. Curr Rheu-matol Rep 2006; 8:145-150. (Pubitemid 44623983)
93. Pilling D, Fan T, Huang D, Kaul B, Gomer RH: Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One 2009; 4:e7475.
94. Schmidt M, Sun G, Stacey MA, Mori L, Mat-toli S: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003; 171:380-389. (Pubitemid 36745311)
95. Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K, Gobel N, Talke Y, Schweda F, Mack M: CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci USA 2009; 106:17892-17897.
96. Sakai N, Furuichi K, Shinozaki Y, Yamauchi H, Toyama T, Kitajima S, Okumura T, Kokubo S, Kobayashi M, Takasawa K, Takeda S, Yoshimura M, Kaneko S, Wada T: Fibrocytes are involved in the pathogenesis of human chronic kidney disease. Hum Pathol 2010; 41: 672-678.
97. Zeisberg M, Neilson EG: Mechanisms of tu-bulointerstitial fibrosis. J Am Soc Nephrol 2010; 21:1819-1834.
98. Grgic I, Duffield JS, Humphreys BD: The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr Nephrol 2012; 27: 183-193.
99. Lin SL, Kisseleva T, Brenner DA, Duffield JS: Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 2008; 173: 1617-1627.
100. Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, Blattner SM, Kretzler M, Strutz F, Mack M, Grone HJ, Onuffer J, Horuk R, Nelson PJ, Schlondorff D: A chemokine receptor CCR-1 antagonist reduces renal fi-brosis after unilateral ureter ligation. J Clin Invest 2002; 109:251-259. (Pubitemid 34083745)
101. Bedke J, Kiss E, Schaefer L, Behnes CL, Bonrouhi M, Gretz N, Horuk R, Diedrichs-Moehring M, Wildner G, Nelson PJ, Grone HJ: Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage. Am J Tra nsplant 2007; 7: 527-537. (Pubitemid 46376438)
102. -/- mice during chronic fungal allergic airway disease. J Immunol 2000; 165: 1564-1572. (Pubitemid 30604593)
103. Eis V, Luckow B, Vielhauer V, Siveke JT, Linde Y, Segerer S, Perez De Lema G, Cohen CD, Kretzler M, Mack M, Horuk R, Murphy PM, Gao JL, Hudkins KL, Alpers CE, Grone HJ, Schlondorff D, Anders HJ: Che-mokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J Am Soc Nephrol 2004; 15: 337-347. (Pubitemid 38140774)
104. Ninichuk V, Anders HJ: Chemokine receptor CCR1: a new target for progressive kidney disease. Am J Nephrol 2005; 25:365-372. (Pubitemid 41160995)
105. Scholten D, Reichart D, Paik YH, Lindert J, Bhattacharya J, Glass CK, Brenner DA, Kis-seleva T: Migration of fibrocytes in fibro-genic liver injury. Am J Pathol 2011; 179: 189-198.
106. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA: CCR2 promotes hepatic fibro-sis in mice. Hepatology 2009; 50: 185-197.
107. Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama T, Matsushima K: Pivotal role of CCR1-positive leukocytes in bleomycin-in-duced lung fibrosis in mice. J Immunol 2000; 164:2745-2751. (Pubitemid 30115508)
108. Vielhauer V, Berning E, Eis V, Kretzler M, Segerer S, Strutz F, Horuk R, Grone HJ, Schlondorff D, Anders HJ: CCR1 blockade reduces interstitial inflammation and fi-brosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int 2004; 66: 2264-2278. (Pubitemid 41115289)
109. Yang Z, Kong B, Mosser DM, Zhang X: TLRs, macrophages, and NK cells: our understandings of their functions in uterus and ovary. Int Immunopharmacol 2011; 11: 1442-1450.
110. 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.
111. Ishida Y, Gao JL, Murphy PM: Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol 2008; 180: 569-579.
112. Fang Y, Shen J, Yao M, Beagley KW, Ham-bly BD, Bao S: Granulocyte-macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines. Br J Dermatol 2010; 162: 478-486.
113. Lu TT: Dendritic cells: novel players in fibrosis and scleroderma. Curr Rheumatol Rep 2012; 14: 30-38.
114. Imamura M, Ogawa T, Sasaguri Y, Chaya-ma K, Ueno H: Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats. Gastroenterology 2005; 128: 138-146. (Pubitemid 40039965)
115. Karlmark KR, Weiskirchen R, Zimmer-mann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F: Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50: 261-274.
116. Vielhauer V, Anders HJ, Mack M, Cihak J, Strutz F, Stangassinger M, Luckow B, Grone HJ, Schlondorff D: Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2-and 5-positive leukocytes. J Am Soc Nephrol 2001; 12:1173-1187. (Pubitemid 32472630)
117. Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Ku-ziel WA, Matsushima K, Mukaida N, Yo-koyama H: Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol 2004; 165: 237-246. (Pubitemid 38821831)
118. Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K, Ishida Y, Kondo T, Hashimoto H, Ishiwata Y, Mukaida N, Tomosugi N, Matsushima K, Egashira K, Yokoyama H: Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol 2004; 15:940-948. (Pubitemid 38375313)
119. Ninichuk V, Clauss S, Kulkarni O, Schmid H, Segerer S, Radomska E, Eulberg D, Buchner K, Selve N, Klussmann S, Anders HJ: Late onset of Ccl2 blockade with the spiegelmer mNOX-E36-3'PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice. Am J Pathol 2008; 172: 628-637. (Pubitemid 351354536)
120. Okuma T, Terasaki Y, Kaikita K, Kobayashi H, Kuziel WA, Kawasuji M, Takeya M: C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases. J Pathol 2004; 204: 594-604. (Pubitemid 39585959)
121. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A: IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fi-brosis. Nat Med 2006; 12:99-106. (Pubitemid 43050083)
122. Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR: A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gas-troenterology 2004; 126:955-963.
123. Andersson-Sjoland A, de Alba CG, Nihl-berg K, Becerril C, Ramirez R, Pardo A, Westergren-Thorsson G, Selman M: Fibro-cytes are a potential source of lung fibro-blasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 2008; 40:2129-2140.
124. van Amerongen MJ, Bou-Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM, van Luyn MJ, Harmsen MC: Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pat hol 2008; 214: 377-386. (Pubitemid 351212393)
125. Occleston NL, O'Kane S, Laverty HG, Cooper M, Fairlamb D, Mason T, Bush JA, Ferguson MW: Discovery and development of avotermin (recombinant human transforming growth factor beta 3): a new class of prophylactic therapeutic for the improvement of scarring. Wound Repair Re-gen 2011; 19(suppl 1):s38-s48.
126. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP: Selective depletion of macro-phages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115: 56-65. (Pubitemid 40385505)
127. Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP: Scar-associated macrophages are a major source of hepatic matrix metal-loproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007; 178:5288-5295. (Pubitemid 46595314)
128. Harty MW, Papa EF, Huddleston HM, Young E, Nazareth S, Riley CA, Ramm GA, Gregory SH, Tracy TF Jr: Hepatic macro-phages promote the neutrophil-dependent resolution of fibrosis in repairing chole-static rat livers. Surgery 2008; 143: 667-678. (Pubitemid 351626112)
129. Jiang D, Liang J, Campanella GS, Guo R, Yu S, Xie T, Liu N, Jung Y, Homer R, Meltzer EB, Li Y, Tager AM, Goetinck PF, Luster AD, Noble PW: Inhibition of pulmonary fi-brosis in mice by CXCL10 requires glycos-aminoglycan binding and syndecan-4. J Clin Invest 2010; 120:2049-2057.
130. Crispe IN: Liver antigen-presenting cells. J Hepatol 2011; 54:357-365.
131. Sathe P, Shortman K: The steady-state development of splenic dendritic cells. Muco-sal Immunol 2008; 1:425-431.
132. Welzen-Coppens JM, van Helden-Meeuw-sen CG, Drexhage HA, Versnel MA: Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes. Eur J Immunol 2012; 42: 186-194.
133. John R, Nelson PJ: Dendritic cells in the kidney. J Am Soc Nephrol 2007; 18: 2628-2635. (Pubitemid 47531188)
134. Nelson PJ, Rees AJ, Griffin MD, Hughes J, Kurts C, Duffield J: The renal mononuclear phagocytic system. J Am Soc Nephrol 2012; 23: 194-203.
135. Ehninger A, Trumpp A: The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. J Exp Med 2011; 208:421-428.
136. Tian DS, Dong Q, Pan DJ, He Y, Yu ZY, Xie MJ, Wang W: Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Res 2007; 1154: 206-214. (Pubitemid 46856341)
137. Leonardo CC, Eakin AK, Ajmo JM, Collier LA, Pennypacker KR, Strongin AY, Gott-schall PE: Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat. J Neuroin-flammation 2008; 5:34.
138. Raivich G, Moreno-Flores MT, Moller JC, Kreutzberg GW: Inhibition of posttrau-matic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. Eur J Neu-rosci 1994; 6:1615-1618. (Pubitemid 24310369)
139. Cardenas H, Bolin LM: Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice. Brain Res 2003; 985:89-97. (Pubitemid 37272055)
140. Tian DS, Xie MJ, Yu ZY, Zhang Q, Wang YH, Chen B, Chen C, Wang W: Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuro-nal cell death after spinal cord injury in rats. Brain Res 2007; 1135:177-185. (Pubitemid 46176818)
141. Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensi-tivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003; 306: 624-630. (Pubitemid 36886161)
142. Spataro L, Dilgen J, Retterer S, Spence AJ, Isaacson M, Turner JN, Shain W: Dexa-methasone treatment reduces astroglia responses to inserted neuroprosthetic devices in rat neocor tex. Exp Neurol 2005; 194: 289-300. (Pubitemid 40966990)
143. Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M: Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 1998; 4: 814-821. (Pubitemid 28331023)
144. Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M: Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci USA 2006; 103: 13174-13179. (Pubitemid 44338935)
145. Mori R, Shaw TJ, Martin P: Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med 2008; 205:43-51. (Pubitemid 351185714)
146. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S: Fibrocy tes contr ibute to the myo-fibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 2005; 304: 81-90. (Pubitemid 40222079)
147. Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, Ghahary A, Tredget EE: Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 2005; 13: 398-404. (Pubitemid 41060421)
148. Belperio JA, Keane MP, Burdick MD, Lynch JP 3rd, Xue YY, Berlin A, Ross DJ, Kunkel SL, Charo IF, Strieter RM: Critical role for the chemokine MCP-1/CCR2 in the patho-genesis of bronchiolitis obliterans syndrome. J Clin Invest 2001; 108: 547-556. (Pubitemid 32777734)
149. Belperio JA, Keane MP, Burdick MD, Lynch JP 3rd, Xue YY, Li K, Ross DJ, Strieter RM: Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliter-ans syndrome. J Immunol 2002; 169:1037-1049. (Pubitemid 34753464)
150. Xing Z, Tremblay GM, Sime PJ, Gauldie J: Overexpression of granulocyte-macro-phage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation. Am J Pathol 1997; 150: 59-66. (Pubitemid 27027096)
151. Atabai K, Jame S, Azhar N, Kuo A, Lam M, McKleroy W, Dehart G, Rahman S, Xia DD, Melton AC, Wolters P, Emson CL, Turner SM, Werb Z, Sheppard D: Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J Clin Invest 2009; 119: 3713-3722.
152. Burdick MD, Murray LA, Keane MP, Xue YY, Zisman DA, Belperio JA, Strieter RM: CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005; 171:261-268.
153. Ryu M, Kulkarni OP, Radomska E, Miosge N, Gross O, Anders HJ: Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-alpha-mediated podoc y te loss. Kidney Int 2011; 79: 189-198.
154. Anders HJ, Frink M, Linde Y, Banas B, Wornle M, Cohen CD, Vielhauer V, Nelson PJ, Grone HJ, Schlondorff D: CC chemo-ki ne ligand 5/R A NTE S chemok ine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration. J Immunol 2003; 170:5658-5666. (Pubitemid 36617858)
155. Castano AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel T, Singh A, Li S, Lupher ML Jr, Duffield JS: Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo. Sci Transl Med 2009; 1: 5ra13.
156. Ninichuk V, Khandoga AG, Segerer S, Loetscher P, Schlapbach A, Revesz L, Fei-fel R, Khandoga A, Krombach F, Nelson PJ, Schlondorff D, Anders HJ: The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice. Am J Pathol 2007; 170:1267-1276. (Pubitemid 47339334)
157. Dehmel S, Wang S, Schmidt C, Kiss E, Loewe RP, Chilla S, Schlondorff D, Grone HJ, Luckow B: Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal al-lograft outcome. Eur J Immunol 2010; 40: 267-278.
158. Wada T, Sakai N, Sakai Y, Matsushima K, Kaneko S, Furuichi K: Involvement of bone-marrow-derived cells in kidney fibro-sis. Clin Exp Nephrol 2011; 15:8-13.
159. Broekema M, Harmsen MC, van Luyn MJ, Koerts JA, Petersen AH, van Kooten TG, van Goor H, Navis G, Popa ER: Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after is-chemia/reperfusion in rats. J Am Soc Ne-phrol 2007; 18: 165-175. (Pubitemid 46053430)
160. Zeisberg M, Hanai J, Sugimoto H, Mam-moto T, Charytan D, Strutz F, Kalluri R: BMP-7 counteracts TGF-beta1-induced ep-ithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964-968. (Pubitemid 36889942)
161. Zeisberg M, Khurana M, Rao VH, Cos-grove D, Rougier JP, Werner MC, Shield CF 3rd, Werb Z, Kalluri R: Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med 2006; 3:e100.
162. Nishida M, Okumura Y, Fujimoto S, Shirai-shi I, Itoi T, Hamaoka K: Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem Biophys Res Commun 2005; 332: 11-16. (Pubitemid 40719450)
163. Marra F, DeFranco R, Grappone C, Parola M, Milani S, Leonarduzzi G, Pastacaldi S, Wenzel UO, Pinzani M, Dianzani MU, Laffi G, Gentilini P: Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E. J In-vestig Med 1999; 47:66-75. (Pubitemid 129537259)
164. Otogawa K, Kinoshita K, Fujii H, Sakabe M, Shiga R, Nakatani K, Ikeda K, Nakajima Y, Ikura Y, Ueda M, Arakawa T, Hato F, Kawa da N: Erythrophagocytosis by liver macro-phages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol 2007; 170: 967-980. (Pubitemid 47339365)
165. Jiang W, Sun R, Wei H, Tian Z: Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci USA 2005; 102:17077-17082. (Pubitemid 41692686)
166. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ: Mechanisms of spontaneous resolution of rat liver fibrosis: hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102: 538-549. (Pubitemid 28376157)
167. Mitchell C, Couton D, Couty JP, Anson M, Crain AM, Bizet V, Renia L, Pol S, Mallet V, Gilgenkrantz H: Dual role of CCR2 in the constitution and the resolution of liver fi-brosis in mice. Am J Pathol 2009; 174:1766-1775.
168. Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J: Effects of gadolinium chloride (GdCl(3)) on the appearance of macro-phage populations and fibrogenesis in thio-acetamide-induced rat hepatic lesions. J Comp Pathol 2005; 133: 92-102. (Pubitemid 41150166)
169. Kisseleva T, Uchinami H, Feirt N, Quin-tana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA: Bone marrow-derived fi-brocytes participate in pathogenesis of liver fibrosis. J Hepatol 2006; 45:429-438. (Pubitemid 44142115)
170. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, Thompson RW, Cheever AW, Murray PJ, Wynn TA: Arginase-1-expressing macro-phages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 2009; 5:e1000371.
171. Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ra-machandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ: Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration and function. Hepatology 2011; 53: 2003-2015.
172. Popov Y, Sverdlov DY, Bhaskar KR, Sharma AK, Millonig G, Patsenker E, Krahenbuhl S, Krahenbuhl L, Schuppan D: Macro-phage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am J Physiol Gastrointest Liver Physiol 2010; 298:G323-G334.
173. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ: The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204: 3037-3047. (Pubitemid 350179569)
174. Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, Wen J, Egashira K, Takeshita A: Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2003; 108:2134-2140. (Pubitemid 37337591)
175. Hayasaki T, Kaikita K, Okuma T, Yamamo-to E, Kuziel WA, Ogawa H, Takeya M: CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice. Circ J 2006; 70:342-351.
176. Segawa M, Fukada S, Yamamoto Y, Yahagi H, Kanematsu M, Sato M, Ito T, Uezumi A, Hayashi S, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Yamamoto H: Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp Cell Res 2008; 314: 3232-3244.
177. Leor J, Rozen L, Zuloff-Shani A, Feinberg MS, Amsalem Y, Barbash IM, Kachel E, Holbova R, Mardor Y, Daniels D, Ochera-shvilli A, Orenstein A, Danon D: Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation 2006; 114:I94-I100. (Pubitemid 44297135)
178. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ: Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol 2007; 170:818-829. (Pubitemid 47339352)
179. Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Crawford JR, Pilling D, Gomer RH, Trial J, Frangogiannis NG, Entman ML: Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA 2006; 103: 18284-18289. (Pubitemid 44871650)
180. Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, Itoh T, Takeshita A: Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol 2003; 285:H1229-H1235. (Pubitemid 37048181)