Role of DAMPs in Tissue Regeneration and Repair

  • Walter Gottlieb Land


This final chapter of Volume 1 is dedicated to the healing process following tissue injury that is one of the characteristic functions of the innate immune system aimed at restoring homeostasis. The two major phases of wound healing consist of initial resolution of inflammation followed by tissue regenerative and repairing processes. A variety of hematopoietic and non-hematopoietic cells of the innate immune system is regarded as the principal regulators of tissue repair and regeneration. These cells include macrophages and myofibroblasts with pronounced fibrogenic properties but also vascular cells, epithelial cells, organ-specific cells such as renal tubular cells and hepatic stellate cells, and, last but not least, stem cells, particularly, mesenchymal stem cells. Increasing evidence from the literature suggests that the activity of all these PRM-bearing cells is regulated and orchestrated by tissue injury-induced emission of DAMPs. However, the failure to resolve inflammation, combined with uncontrolled overshooting repairing pathways, leads to tissue remodelling rather than tissue regeneration, which is clinically termed as tissue fibrosis or sclerosis. This deleterious development of a progressively irreversible fibrotic response may occur when the well-defined and fine-tuned chronology of regulated inflammatory events needed for optimal repair gets out of control. These new insights into mechanisms of DAMP-promoted regenerative and repairing mechanisms are increasingly understood. Deciphering the action of DAMPs according to the nature and strength of a given perpetual or chronic repetitive injury may become the key in interfering with those deleteriously overshooting repairing processes and, thus, could open new avenues of treatment or even prevention of chronic fibrotic/sclerotic disorders such as atherosclerosis.


  1. 1.
    Julier Z, Park AJ, Briquez PS, Martino MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017;53:13–28. Available from: PubMedCrossRefGoogle Scholar
  2. 2.
    Song Z, Gupta K, Ng IC, Xing J, Yang YA, Yu H. Mechanosensing in liver regeneration. Semin Cell Dev Biol. 2017. Available from: CrossRefGoogle Scholar
  3. 3.
    Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20:857–69. Scholar
  4. 4.
    Land W. Allograft injury mediated by reactive oxygen species: from conserved proteins of drosophila to acute and chronic rejection of human transplants. Part III: interaction of (oxidative) stress-induced heat shock proteins with toll-like receptor-bearing cells. Transplant Rev. 2003;17:67–86. Available from: CrossRefGoogle Scholar
  5. 5.
    Godwin JW, Pinto AR, Rosenthal NA. Chasing the recipe for a pro-regenerative immune system. Semin Cell Dev Biol. 2017;61:71–9. Available from: PubMedCrossRefGoogle Scholar
  6. 6.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210. Scholar
  7. 7.
    Meng X-M, Tang PM-K, Li J, Lan HY. Macrophage phenotype in kidney injury and repair. Kidney Dis (Basel, Switzerland). 2015;1:138–46. Available from: Google Scholar
  8. 8.
    Sun Y-Y, Li X-F, Meng X-M, Huang C, Zhang L, Li J. Macrophage phenotype in liver injury and repair. Scand J Immunol. 2016;85(3):166–74. Available from: CrossRefGoogle Scholar
  9. 9.
    Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44:450–62. Available from: CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013;229:298–309. Available from: CrossRefGoogle Scholar
  11. 11.
    Micera A, Balzamino BO, Di Zazzo A, Biamonte F, Sica G, Bonini S. Toll-like receptors and tissue remodeling: the pro/cons recent findings. J Cell Physiol. 2016;231:531–44. Available from: PubMedCrossRefGoogle Scholar
  12. 12.
    Darby IA, Zakuan N, Billet F, Desmoulière A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci. 2016;73:1145–57. Available from: PubMedCrossRefGoogle Scholar
  13. 13.
    He J, Xiao Z, Chen X, Chen M, Fang L, Yang M, et al. The expression of functional Toll-like receptor 4 is associated with proliferation and maintenance of stem cell phenotype in endothelial progenitor cells (EPCs). J Cell Biochem. 2010;111:179–86. Available from: PubMedCrossRefGoogle Scholar
  14. 14.
    Wanjare M, Kusuma S, Gerecht S. Perivascular cells in blood vessel regeneration. Biotechnol J. 2013;8:434–47. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Psaltis PJ, Simari RD. Vascular wall progenitor cells in health and disease. Circ Res. 2015;116:1392–412. Available from: PubMedCrossRefGoogle Scholar
  16. 16.
    Salvador B, Arranz A, Francisco S, Córdoba L, Punzón C, Llamas MÁ, et al. Modulation of endothelial function by Toll like receptors. Pharmacol Res. 2016;108:46–56. Available from: PubMedCrossRefGoogle Scholar
  17. 17.
    Portou MJJ, Baker D, Abraham D, Tsui J. The innate immune system, toll-like receptors and dermal wound healing: a review. Vascul Pharmacol. 2015;71:31–6. Available from: PubMedCrossRefGoogle Scholar
  18. 18.
    Hato T, El-Achkar TM, Dagher PC. isters in arms: myeloid and tubular epithelial cells shape renal innate immunity. Am J Physiol Renal Physiol. 2013;304:F1243–51. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr. 2014;3:344–63. Available from: PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hwa Cho H, Bae YC, Jung JS. Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells. 2006;24:2744–52. Available from: PubMedCrossRefGoogle Scholar
  21. 21.
    Delarosa O, Dalemans W, Lombardo E. Toll-like receptors as modulators of mesenchymal stem cells. Front Immunol. 2012;3:182. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16:907–17. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, et al. Fibronectin EDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci Transl Med. 2014;6:232ra50. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lee C-C, Wang C-N, Lee Y-L, Tsai Y-R, Liu J-J. High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. PLoS One. 2015;10:e0116393. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ranzato E, Patrone M, Pedrazzi M, Burlando B. Hmgb1 promotes wound healing of 3T3 mouse fibroblasts via RAGE-dependent ERK1/2 activation. Cell Biochem Biophys. 2010;57:9–17. Available from: PubMedCrossRefGoogle Scholar
  26. 26.
    De Mori R, Straino S, Di Carlo A, Mangoni A, Pompilio G, Palumbo R, et al. Multiple effects of high mobility group box protein 1 in skeletal muscle regeneration. Arterioscler Thromb Vasc Biol. 2007;27:2377–83. Available from: PubMedCrossRefGoogle Scholar
  27. 27.
    Zabini D, Crnkovic S, Xu H, Tscherner M, Ghanim B, Klepetko W, et al. High-mobility group box-1 induces vascular remodelling processes via c-Jun activation. J Cell Mol Med. 2015;19:1151–61. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kao Y-H, Jawan B, Goto S, Hung C-T, Lin Y-C, Nakano T, et al. High-mobility group box 1 protein activates hepatic stellate cells in vitro. Transplant Proc. 2008;40:2704–5. Available from: PubMedCrossRefGoogle Scholar
  29. 29.
    Pistoia V, Raffaghello L. Damage-associated molecular patterns (DAMPs) and mesenchymal stem cells: a matter of attraction and excitement. Eur J Immunol. 2011;41:1828–31. Available from: PubMedCrossRefGoogle Scholar
  30. 30.
    Lotfi R, Eisenbacher J, Solgi G, Fuchs K, Yildiz T, Nienhaus C, et al. Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material. Eur J Immunol. 2011;41:2021–8. Available from: PubMedCrossRefGoogle Scholar
  31. 31.
    Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20:14–20. Available from: PubMedCrossRefGoogle Scholar
  32. 32.
    Eisenbacher JL, Schrezenmeier H, Jahrsdörfer B, Kaltenmeier C, Rojewski MT, Yildiz T, et al. S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes. J Immunol. 2014;192:6102–10. Available from: PubMedCrossRefGoogle Scholar
  33. 33.
    Mahrouf-Yorgov M, Augeul L, Da Silva CC, Jourdan M, Rigolet M, Manin S, et al. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 2017;24:1224–38. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118:692–702. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Lim S, Park S. Role of vascular smooth muscle cell in the inflammation of atherosclerosis. BMB Rep. 2014;47:1–7. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rai V, Agrawal DK. The role of DAMPs and PAMPs in inflammation-mediated vulnerability of atherosclerotic plaques. Can J Physiol Pharmacol. 2017;95:1245–53. Available from: PubMedCrossRefGoogle Scholar
  37. 37.
    Duann P, Lianos EA, Ma J, Lin P-H. Autophagy, innate immunity and tissue repair in acute kidney injury. Int J Mol Sci. 2016;17. Available from: Scholar
  38. 38.
    Hou W, Zhang Q, Yan Z, Chen R, Zeh Iii HJ, Kang R, et al. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 2013;4:e966. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Li G, Tang D, Lotze MT. Ménage à Trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol. 2013;23:380–90. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Vénéreau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. 2015;6:422. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Tamai K, Yamazaki T, Chino T, Ishii M, Otsuru S, Kikuchi Y, et al. PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci U S A. 2011;108:6609–14. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Feng L, Xue D, Chen E, Zhang W, Gao X, Yu J, et al. HMGB1 promotes the secretion of multiple cytokines and potentiates the osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway. Exp Ther Med. 2016;12:3941–7. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–65. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kitahara T, Takeishi Y, Harada M, Niizeki T, Suzuki S, Sasaki T, et al. High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice. Cardiovasc Res. 2008;80:40–6. Available from: PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang W, Lavine KJ, Epelman S, Evans SA, Weinheimer CJ, Barger PM, et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc. 2015;4:e001993. Available from: PubMedPubMedCentralGoogle Scholar
  46. 46.
    Kao Y-H, Lin Y-C, Tsai M-S, Sun C-K, Yuan S-S, Chang C-Y, et al. Involvement of the nuclear high mobility group B1 peptides released from injured hepatocytes in murine hepatic fibrogenesis. Biochim Biophys Acta. 2014;1842:1720–32. Available from: PubMedCrossRefGoogle Scholar
  47. 47.
    Yang S, Xu L, Yang T, Wang F. High-mobility group box-1 and its role in angiogenesis. J Leukoc Biol. 2014;95:563–74. Available from: PubMedCrossRefGoogle Scholar
  48. 48.
    Chavakis E, Hain A, Vinci M, Carmona G, Bianchi ME, Vajkoczy P, et al. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res. 2007;100:204–12. Available from: PubMedCrossRefGoogle Scholar
  49. 49.
    Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, et al. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 2006;176:12–5. Available from: PubMedCrossRefGoogle Scholar
  50. 50.
    Nass N, Trau S, Paulsen F, Kaiser D, Kalinski T, Sel S. The receptor for advanced glycation end products RAGE is involved in corneal healing. Ann Anat. 2017;211:13–20. Available from: PubMedCrossRefGoogle Scholar
  51. 51.
    van Beijnum JR, Nowak-Sliwinska P, van den Boezem E, Hautvast P, Buurman WA, Griffioen AW. Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene. 2013;32:363–74. Available from: PubMedCrossRefGoogle Scholar
  52. 52.
    Campana L, Santarella F, Esposito A, Maugeri N, Rigamonti E, Monno A, et al. Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles. J Immunol. 2014;192:5257–64. Available from: PubMedCrossRefGoogle Scholar
  53. 53.
    Nakamura Y, Suzuki S, Shimizu T, Miyata M, Shishido T, Ikeda K, et al. High mobility group box 1 promotes angiogenesis from bone marrow-derived endothelial progenitor cells after myocardial infarction. J Atheroscler Thromb. 2015;22:570–81. Available from: PubMedCrossRefGoogle Scholar
  54. 54.
    Chen J-Y, Yu Y, Yuan Y, Zhang Y-J, Fan X-P, Yuan S-Y, et al. Enriched housing promotes post-stroke functional recovery through astrocytic HMGB1-IL-6-mediated angiogenesis. Cell Death Discov. 2017;3:17054. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhou J, Chen X, Gilvary DL, Tejera MM, Eksioglu EA, Wei S, et al. HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells. Sci Rep. 2015;5:15085. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Nguan CYC, Guan Q, Gleave ME, Du C. Promotion of cell proliferation by clusterin in the renal tissue repair phase after ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2014;306:F724–33. Available from: PubMedCrossRefGoogle Scholar
  57. 57.
    Guo J, Guan Q, Liu X, Wang H, Gleave ME, Nguan CYC, et al. Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury. BMC Nephrol. 2016;17:133. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ojo OO, Ryu MH, Jha A, Unruh H, Halayko AJ. High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1354–66. Available from: PubMedCrossRefGoogle Scholar
  59. 59.
    Cai J, Yuan H, Wang Q, Yang H, Al-Abed Y, Hua Z, et al. HMGB1-driven inflammation and intimal hyperplasia after arterial injury involves cell-specific actions mediated by TLR4Significance. Arterioscler Thromb Vasc Biol. 2015;35:2579–93. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. Functions of S100 proteins. Curr Mol Med. 2013;13:24–57. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Reimann S, Fink L, Wilhelm J, Hoffmann J, Bednorz M, Seimetz M, et al. Increased S100A4 expression in the vasculature of human COPD lungs and murine model of smoke-induced emphysema. Respir Res. 2015;16:127. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Choe N, Kwon D-H, Shin S, Kim YS, Kim Y-K, Kim J, et al. The microRNA miR-124 inhibits vascular smooth muscle cell proliferation by targeting S100 calcium-binding protein A4 (S100A4). FEBS Lett. 2017;591:1041–52. Available from: PubMedCrossRefGoogle Scholar
  63. 63.
    Bekos C, Zimmermann M, Unger L, Janik S, Hacker P, Mitterbauer A, et al. Non-professional marathon running: RAGE axis and ST2 family changes in relation to open-window effect, inflammation and renal function. Sci Rep. 6:32315. Available from:
  64. 64.
    Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014;509:310–7. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009;461:282–6. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science. 2006;314:1792–5. Available from: PubMedCrossRefGoogle Scholar
  67. 67.
    Yu N, Erb L, Shivaji R, Weisman GA, Seye CI. Binding of the P2Y2 nucleotide receptor to filamin A regulates migration of vascular smooth muscle cells. Circ Res. 2008;102:581–8. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Satterwhite CM, Farrelly AM, Bradley ME. Chemotactic, mitogenic, and angiogenic actions of UTP on vascular endothelial cells. Am J Phys. 1999;276:H1091–7. Available from: CrossRefGoogle Scholar
  69. 69.
    Jin H, Seo J, Eun SY, Joo YN, Park SW, Lee JH, et al. P2Y2 R activation by nucleotides promotes skin wound-healing process. Exp Dermatol. 2014;23:480–5. Available from: PubMedCrossRefGoogle Scholar
  70. 70.
    Zhou Z, Chrifi I, Xu Y, Pernow J, Duncker DJ, Merkus D, et al. Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors. Am J Physiol Heart Circ Physiol. 2016;311:H299–309. Available from: PubMedCrossRefGoogle Scholar
  71. 71.
    Negro S, Bergamin E, Rodella U, Duregotti E, Scorzeto M, Jalink K, et al. ATP released by injured neurons activates Schwann cells. Front Cell Neurosci. 2016;10:134. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Nakagawa S, Omura T, Yonezawa A, Yano I, Nakagawa T, Matsubara K. Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury. Am J Physiol Renal Physiol. 2014;307:F1404–11. Available from: PubMedCrossRefGoogle Scholar
  73. 73.
    Gonzales E, Julien B, Serrière-Lanneau V, Nicou A, Doignon I, Lagoudakis L, et al. ATP release after partial hepatectomy regulates liver regeneration in the rat. J Hepatol. 2010;52:54–62. Available from: PubMedCrossRefGoogle Scholar
  74. 74.
    Ando T, Ito H, Kanbe A, Hara A, Seishima M. Deficiency of NALP3 signaling impairs liver regeneration after partial hepatectomy. Inflammation. 2017;40(5):1717–25. Available from: PubMedCrossRefGoogle Scholar
  75. 75.
    Artlett CM. The role of the NLRP3 inflammasome in fibrosis. Open Rheumatol J. 2012;6:80–6. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123:594–604. Available from: PubMedCrossRefGoogle Scholar
  77. 77.
    Wang W, Wang X, Chun J, Vilaysane A, Clark S, French G, et al. Inflammasome-independent NLRP3 augments TGF-β signaling in kidney epithelium. J Immunol. 2013;190:1239–49. Available from: PubMedCrossRefGoogle Scholar
  78. 78.
    Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol. 2007;34:146–53. Available from: PubMedCrossRefGoogle Scholar
  79. 79.
    Gasse P, Riteau N, Charron S, Girre S, Fick L, Pétrilli V, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med. 2009;179:903–13. Available from: PubMedCrossRefGoogle Scholar
  80. 80.
    Riteau N, Gasse P, Fauconnier L, Gombault A, Couegnat M, Fick L, et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Care Med. 2010;182:774–83. Available from: PubMedCrossRefGoogle Scholar
  81. 81.
    Fix C, Bingham K, Carver W. Effects of interleukin-18 on cardiac fibroblast function and gene expression. Cytokine. 2011;53:19–28. Available from: PubMedCrossRefGoogle Scholar
  82. 82.
    Boza P, Ayala P, Vivar R, Humeres C, Cáceres FT, Muñoz C, et al. Expression and function of toll-like receptor 4 and inflammasomes in cardiac fibroblasts and myofibroblasts: IL-1β synthesis, secretion, and degradation. Mol Immunol. 2016;74:96–105. Available from: PubMedCrossRefGoogle Scholar
  83. 83.
    Mia MM, Boersema M, Bank RA. Interleukin-1β attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-β1. PLoS One. 2014;9:e91559. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Artlett CM, Thacker JD. Molecular activation of the NLRP3 inflammasome in fibrosis: common threads linking divergent fibrogenic diseases. Antioxid Redox Signal. 2015;22:1162–75. Available from: PubMedCrossRefGoogle Scholar
  85. 85.
    Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K. Toll-like receptors as a key regulator of mesenchymal stem cell function: an up-to-date review. Cell Immunol. 2017;315:1–10. Available from: PubMedCrossRefGoogle Scholar
  86. 86.
    Schäfer R, Spohn G, Baer PC. Mesenchymal stem/stromal cells in regenerative medicine: can preconditioning strategies improve therapeutic efficacy? Transfus Med Hemother. 2016;43:256–67. Scholar
  87. 87.
    Land WG. Chronic allograft dysfunction: a model disorder of innate immunity. Biomed J. 2013;36:209–28. Available from: PubMedCrossRefGoogle Scholar
  88. 88.
    Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res. 2015;116:307–11. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Gisterå A, Hansson GK. The immunology of atherosclerosis. Nat Rev Nephrol. 2017;13:368–80. Available from: PubMedCrossRefGoogle Scholar
  90. 90.
    Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40. Scholar
  91. 91.
    Mercer PF, Chambers RC. Coagulation and coagulation signalling in fibrosis. Biochim Biophys Acta. 2013;1832:1018–27. Available from: PubMedCrossRefGoogle Scholar
  92. 92.
    Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol. 1997;151:317–22. Available from: PubMedPubMedCentralGoogle Scholar
  93. 93.
    Lee K, Nelson CM. New insights into the regulation of epithelial–mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol. 2012;294:171–221. Available from: PubMedCrossRefGoogle Scholar
  94. 94.
    Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Latent TGF-β-binding proteins. Matrix Biol. 2015;47:44–53. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Taylor AW. Review of the activation of TGF- in immunity. J Leukoc Biol. 2008;85:29–33. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jain M, Rivera S, Monclus EA, Synenki L, Zirk A, Eisenbart J, et al. Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. J Biol Chem. 2013;288:770–7. Scholar
  97. 97.
    Henderson NC, Sheppard D. Integrin-mediated regulation of TGFβ in fibrosis. Biochim Biophys Acta. 1832;2013:891–6. Available from: Google Scholar
  98. 98.
    Fujio K, Komai T, Inoue M, Morita K, Okamura T, Yamamoto K. Revisiting the regulatory roles of the TGF-β family of cytokines. Autoimmun Rev. 2016;15:917–22. Available from: PubMedCrossRefGoogle Scholar
  99. 99.
    Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors. 2011;29:196–202. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Gunaratne A, Chan E, El-Chabib TH, Carter D, Di Guglielmo GM. aPKC alters the TGF response in NSCLC cells through both Smad-dependent and Smad-independent pathways. J Cell Sci. 2015;128:487–98. Available from: PubMedCrossRefGoogle Scholar
  101. 101.
    Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol. 1993;150:4188–96. Available from: PubMedGoogle Scholar
  102. 102.
    Lafyatis R, Farina A. New insights into the mechanisms of innate immune receptor signalling in fibrosis. Open Rheumatol J. 2012;6:72–9. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Pulskens WP, Rampanelli E, Teske GJ, Butter LM, Claessen N, Luirink IK, et al. TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury. J Am Soc Nephrol. 2010;21:1299–308. Scholar
  104. 104.
    Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair. 2010;3:21. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Braga TT, Correa-Costa M, Guise YFS, 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;18:1231–9. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Booth AJ, Wood SC, Cornett AM, Dreffs AA, Lu G, Muro AF, et al. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis. J Pathol. 2012;226:609–18. Scholar
  107. 107.
    Hogaboam CM, Trujillo G, Martinez FJ. Aberrant innate immune sensing leads to the rapid progression of idiopathic pulmonary fibrosis. Fibrogenesis Tissue Repair. 2012;5:S3. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Bhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182:192–205. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Bai T, Lian L-H, Wu Y-L, Wan Y, Nan J-X. Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells. Int Immunopharmacol. 2013;15:275–81. Available from: PubMedCrossRefGoogle Scholar
  110. 110.
    Kelly C, Canning P, Buchanan PJ, Williams MT, Brown V, Gruenert DC, et al. Toll-like receptor 4 is not targeted to the lysosome in cystic fibrosis airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2013;304:L371–82. Scholar
  111. 111.
    Englert JM, Kliment CR, Ramsgaard L, Milutinovic PS, Crum L, Tobolewski JM, et al. Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis. Int J Clin Exp Pathol. 2011;4:241–54. Available from: PubMedPubMedCentralGoogle Scholar
  112. 112.
    Iracheta-Vellve A, Petrasek J, Gyongyosi B, Satishchandran A, Lowe P, Kodys K, et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. J Biol Chem. 2016;291:26794–805. Scholar
  113. 113.
    Ge W-S, Wu J-X, Fan J-G, Wang Y-J, Chen Y-W. Inhibition of high-mobility group box 1 expression by siRNA in rat hepatic stellate cells. World J Gastroenterol. 2011;17:4090–8. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Yin J, Su Z, Wang Y, Wang T, Tian S, Xu X, et al. Release of HMGB1 by LPS-treated cardiac fibroblasts and its contribution to the production of collagen type I and III. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2012;28:785–8. Available from: PubMedGoogle Scholar
  115. 115.
    Lynch J, Nolan S, Slattery C, Feighery R, Ryan MP, McMorrow T. High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition. Am J Nephrol. 2010;32:590–602. Scholar
  116. 116.
    Li L-C, Li D-L, Xu L, Mo X-T, Cui W-H, Zhao P, et al. High-mobility group box 1 mediates epithelial-to-Mesenchymal transition in pulmonary fibrosis involving transforming growth factor- 1/Smad2/3 signaling. J Pharmacol Exp Ther. 2015;354:302–9. Available from: PubMedCrossRefGoogle Scholar
  117. 117.
    Wang Q, Wang J, Wang J, Hong S, Han F, Chen J, et al. HMGB1 induces lung fibroblast to myofibroblast differentiation through NF-κB-mediated TGF-β1 release. Mol Med Rep. 2017;15:3062–8. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Zhong A, Xu W, Zhao J, Xie P, Jia S, Sun J, et al. S100A8 and S100A9 are induced by decreased hydration in the epidermis and promote fibroblast activation and fibrosis in the dermis. Am J Pathol. 2016;186:109–22. PubMedCrossRefGoogle Scholar
  119. 119.
    Zhao J, Zhong A, Friedrich EE, Jia S, Xie P, Galiano RD, et al. S100A12 induced in the epidermis by reduced hydration activates dermal fibroblasts and causes dermal fibrosis. J Invest Dermatol. 2017;137:650–9. Available from: PubMedCrossRefGoogle Scholar
  120. 120.
    Chen L, Li J, Zhang J, Dai C, Liu X, Wang J, et al. S100A4 promotes liver fibrosis via activation of hepatic stellate cells. J Hepatol. 2015;62:156–64. Available from: PubMedCrossRefGoogle Scholar
  121. 121.
    Cai W-F, Zhang X-W, Yan H-M, Ma Y-G, Wang X-X, Yan J, et al. Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice. Cardiovasc Res. 2010;88:140–9. Available from: PubMedCrossRefGoogle Scholar
  122. 122.
    Sörensen I, Susnik N, Inhester T, Degen JL, Melk A, Haller H, et al. Fibrinogen, acting as a mitogen for tubulointerstitial fibroblasts, promotes renal fibrosis. Kidney Int. 2011;80:1035–44. Available from: PubMedCrossRefGoogle Scholar
  123. 123.
    Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology. 2015;61:1066–79. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D. Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res. 2011;9:589–602. Scholar
  125. 125.
    Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, et al. IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010;11:997–1004. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Bostanci N, Meier A, Guggenheim B, Belibasakis GN. Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms. Cell Immunol. 2011;270:88–93. Available from: PubMedCrossRefGoogle Scholar
  127. 127.
    Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick CA, Katsikis PD. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum. 2011;63:3563–74. Scholar
  128. 128.
    Robert S, Gicquel T, Victoni T, Valenca S, Barreto E, Bailly-Maitre B, et al. Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis. Biosci Rep. 2016;36:e00360. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Postlethwaite AE, Raghow R, Stricklin GP, Poppleton H, Seyer JM, Kang AH. Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin 1 alpha and beta. J Cell Biol. 1988;106:311–8. Available from: PubMedCrossRefGoogle Scholar
  130. 130.
    Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207:535–52. Scholar
  131. 131.
    Gasse P, Riteau N, Vacher R, Michel M-L, Fautrel A, di Padova F, et al. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PLoS One. 2011;6:e23185. Scholar
  132. 132.
    Dong Z, Kang Q, Lei W, Zhong H, Tai W, Wang D. Effects of interleukin-17 on murine pulmonary fibroblast proliferation, transformation and collagen synthesis. Nan Fang Yi Ke Da Xue Xue Bao. 2012;32:75–9. Available from: PubMedGoogle Scholar
  133. 133.
    Okamoto Y, Hasegawa M, Matsushita T, Hamaguchi Y, Le HD, Iwakura Y, et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 2012;64:3726–35. Scholar
  134. 134.
    Aoki H, Ohnishi H, Hama K, Ishijima T, Satoh Y, Hanatsuka K, et al. Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells. Am J Physiol Cell Physiol. 2006;290:C1100–8. Scholar
  135. 135.
    Markovics JA, Araya J, Cambier S, Somanath S, Gline S, Jablons D, et al. Interleukin-1beta induces increased transcriptional activation of the transforming growth factor-beta-activating integrin subunit beta8 through altering chromatin architecture. J Biol Chem. 2011;286:36864–74. Scholar
  136. 136.
    Kitamura H, Cambier S, Somanath S, Barker T, Minagawa S, Markovics J, et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β. J Clin Invest. 2011;121:2863–75. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Ness-Schwickerath KJ, Jin C, Morita CT. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells. J Immunol. 2010;184:7268–80. Scholar
  138. 138.
    Caccamo N, La Mendola C, Orlando V, Meraviglia S, Todaro M, Stassi G, et al. Differentiation, phenotype, and function of interleukin-17-producing human V 9V 2 T cells. Blood. 2011;118:129–38. Available from: PubMedCrossRefGoogle Scholar
  139. 139.
    Mills KHG, Dungan LS, Jones SA, Harris J. The role of inflammasome-derived IL-1 in driving IL-17 responses. J Leukoc Biol. 2013;93:489–97. Scholar
  140. 140.
    Peral de Castro C, Jones SA, Ní Cheallaigh C, Hearnden CA, Williams L, Winter J, et al. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. J Immunol. 2012;189:4144–53. Scholar
  141. 141.
    Sutton CE, Mielke LA, Mills KHG. IL-17-producing γδ T cells and innate lymphoid cells. Eur J Immunol. 2012;42:2221–31. Scholar
  142. 142.
    Havenar-Daughton C, Li S, Benlagha K, Marie JC. Development and function of murine RORγt+ iNKT cells are under TGF-β signaling control. Blood. 2012;119:3486–94. Scholar
  143. 143.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33. Available from: CrossRefGoogle Scholar
  144. 144.
    Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–41. Available from: CrossRefGoogle Scholar
  145. 145.
    Bank I. The role of γδ T cells in fibrotic diseases. Rambam Maimonides Med J. 2016;7:e0029. Available from: PubMedCentralCrossRefPubMedGoogle Scholar
  146. 146.
    Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells. Am J Pathol. 2012;181:8–18. Available from: PubMedCrossRefGoogle Scholar
  147. 147.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–4. Scholar
  148. 148.
    Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134:392–404. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9:641–9. Scholar
  150. 150.
    Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9:650–7. Scholar
  151. 151.
    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517. Scholar
  152. 152.
    Huang G, Wang Y, Chi H. Regulation of TH17 cell differentiation by innate immune signals. Cell Mol Immunol. 2012;9:287–95. Scholar
  153. 153.
    Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34:396–408. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Sutton C, Brereton C, Keogh B, Mills KHG, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med. 2006;203:1685–91. Scholar
  155. 155.
    Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature. 2012;484:514–8. Scholar
  156. 156.
    Jones SA, Mills KHG, Harris J. Autophagy and inflammatory diseases. Immunol Cell Biol. 2013;91:250–8. Available from: PubMedCrossRefGoogle Scholar
  157. 157.
    Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2017;18(1):62–76. Available from: PubMedCrossRefGoogle Scholar
  158. 158.
    Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002;8:885–9. Scholar
  159. 159.
    Lee JH, Kaminski N, Dolganov G, Grunig G, Koth L, Solomon C, et al. Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types. Am J Respir Cell Mol Biol. 2001;25:474–85. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University of StrasbourgMolecular ImmunoRheumatology, Laboratory of Excellence TransplantexStrasbourgFrance

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