Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Reparative inflammation takes charge of tissue regeneration

Nature volume 529, pages 307–315 (2016)Cite this article

Subjects

Abstract

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The microanatomy of the cellular compartments responsible for intestinal and liver regeneration.
Figure 2: Mechanisms through which infection and injury induce a regenerative inflammatory response.
Figure 3: Signalling pathways in inflammation-driven regeneration.

Similar content being viewed by others

References

  1. Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274–284 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011). This paper outlines how Paneth cells provide support for ISCs.

    ADS  CAS  PubMed  Google Scholar 

  3. Durand, A. et al. Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc. Natl Acad. Sci. USA 109, 8965–8970 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yang, J. et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt–Wnt situation! Hepatology 60, 964–976 (2014).

    CAS  PubMed  Google Scholar 

  5. Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524, 180–185 (2015). This paper describes a population of diploid pericentral hepatocytes that may act as adult liver stem cells.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stanger, B. Z. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 77, 179–200 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sun, G. & Irvine, K. D. Control of growth during regeneration. Curr. Top. Dev. Biol. 108, 95–120 (2014).

    CAS  PubMed  Google Scholar 

  8. Monga, S. P. Role and regulation of β-catenin signaling during physiological liver growth. Gene Expr. 16, 51–62 (2014).

    PubMed  Google Scholar 

  9. Hu, M. et al. Wnt/β-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 133, 1579–1591 (2007).

    CAS  PubMed  Google Scholar 

  10. Farber, E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3′-methyl-4-dimethylaminoazobenzene. Cancer Res. 16, 142–148 (1956).

    CAS  PubMed  Google Scholar 

  11. Popper, H., Kent, G. & Stein, R. Ductular cell reaction in the liver in hepatic injury. J. Mt. Sinai Hosp. 24, 551–556 (1957).

    CAS  Google Scholar 

  12. West, N. R., McCuaig, S., Franchini, F. & Powrie, F. Emerging cytokine networks in colorectal cancer. Nature Rev. Immunol. 15, 615–629 (2015).

    CAS  Google Scholar 

  13. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Stramer, B. M., Mori, R. & Martin, P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J. Invest. Dermatol. 127, 1009–1017 (2007).

    CAS  PubMed  Google Scholar 

  15. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    ADS  CAS  PubMed  Google Scholar 

  16. Panayidou, S. & Apidianakis, Y. Regenerative inflammation: lessons from Drosophila intestinal epithelium in health and disease. Pathogens 2, 209–231 (2013).

    PubMed  PubMed Central  Google Scholar 

  17. Shaukat, Z., Liu, D. & Gregory, S. Sterile inflammation in Drosophila. Mediators Inflamm. 2015, 369286 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. Buchon, N., Silverman, N. & Cherry, S. Immunity in Drosophila melanogaster — from microbial recognition to whole-organism physiology. Nature Rev. Immunol. 14, 796–810 (2014).

    CAS  Google Scholar 

  19. Ayyaz, A. & Jasper, H. Intestinal inflammation and stem cell homeostasis in aging Drosophila melanogaster. Front. Cell Infect. Microbiol. 3, 98 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Clevers, H., Loh, K. M. & Nusse, R. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346, 1248012 (2014).

    PubMed  Google Scholar 

  21. Xu, N. et al. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells. Dev. Biol. 354, 31–43 (2011).

    CAS  PubMed  Google Scholar 

  22. Cordero, J. B., Stefanatos, R. K., Scopelliti, A., Vidal, M. & Sansom, O. J. Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila. EMBO J. 31, 3901–3917 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K. & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sommer, F. & Backhed, F. The gut microbiota — masters of host development and physiology. Nature Rev. Microbiol. 11, 227–238 (2013).

    CAS  Google Scholar 

  25. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Neu, J. & Walker, W. A. Necrotizing enterocolitis. N. Engl. J. Med. 364, 255–264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004). This is one of the first reports to describe the role of TLR4 signalling in control of mucosal homeostasis.

    CAS  PubMed  Google Scholar 

  28. Neurath, M. F. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol. 7, 6–19 (2014).

    CAS  PubMed  Google Scholar 

  29. Claud, E. C. Neonatal necrotizing enterocolitis — inflammation and intestinal immaturity. Antiinflamm. Antiallergy Agents Med. Chem. 8, 248–259 (2009).

    CAS  Google Scholar 

  30. Lee, W. J. & Brey, P. T. How microbiomes influence metazoan development: insights from history and Drosophila modeling of gut–microbe interactions. Annu. Rev. Cell Dev. Biol. 29, 571–592 (2013).

    CAS  PubMed  Google Scholar 

  31. Cornell, R. P., Liljequist, B. L. & Bartizal, K. F. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice. Hepatology 11, 916–922 (1990).

    CAS  PubMed  Google Scholar 

  32. Seki, E. et al. Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration. Hepatology 41, 443–450 (2005). This is one of the first accounts of the control of liver regeneration by TLR signalling.

    CAS  PubMed  Google Scholar 

  33. Rayes, N. et al. Effect of pre- and probiotics on liver regeneration after resection: a randomised, double-blind pilot study. Benef. Microbes 3, 237–244 (2012).

    CAS  PubMed  Google Scholar 

  34. Taub, R. Liver regeneration: from myth to mechanism. Nature Rev. Mol. Cell Biol. 5, 836–847 (2004).

    CAS  Google Scholar 

  35. Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274, 1379–1383 (1996). This key paper describes the regenerative function of IL-6.

    ADS  CAS  PubMed  Google Scholar 

  36. DeAngelis, R. A. et al. A complement-IL-4 regulatory circuit controls liver regeneration. J. Immunol. 188, 641–648 (2012).

    CAS  PubMed  Google Scholar 

  37. Rock, K. L., Latz, E., Ontiveros, F. & Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Elliott, E. I. & Sutterwala, F. S. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol. Rev. 265, 35–52 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367–378 (2010).

    CAS  PubMed  Google Scholar 

  40. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lopetuso, L. R., Chowdhry, S. & Pizarro, T. T. Opposing functions of classic and novel IL-1 family members in gut health and disease. Front. Immunol. 4, 181 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1–13 (2015).

    Google Scholar 

  43. Stevens, L. J. & Page-McCaw, A. A secreted MMP is required for re-epithelialization during wound healing. Mol. Biol. Cell 23, 1068–1079 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chalaris, A. et al. Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J. Exp. Med. 207, 1617–1624 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Scheller, J., Chalaris, A., Garbers, C. & Rose-John, S. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol. 32, 380–387 (2011).

    CAS  PubMed  Google Scholar 

  46. Yamada, Y., Kirillova, I., Peschon, J. J. & Fausto, N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc. Natl Acad. Sci. USA 94, 1441–1446 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu, Z. G., Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87, 565–576 (1996).

    CAS  PubMed  Google Scholar 

  48. Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274, 782–784 (1996).

    ADS  CAS  PubMed  Google Scholar 

  49. Kamata, H. et al. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649–661 (2005).

    CAS  PubMed  Google Scholar 

  50. Marshall, K. M., He, S., Zhong, Z., Atkinson, C. & Tomlinson, S. Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy. J. Exp. Med. 211, 1793–1805 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen, L. W. et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nature Med. 9, 575–581 (2003). This is the first account of the crucial protective and regenerative function of TNF-induced intestinal NF-κB.

    CAS  PubMed  Google Scholar 

  52. Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004).

    CAS  PubMed  Google Scholar 

  54. Bohm, F., Kohler, U. A., Speicher, T. & Werner, S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol. Med. 2, 294–305 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Akerman, P. et al. Antibodies to tumor necrosis factor-α inhibit liver regeneration after partial hepatectomy. Am. J. Physiol. 263, G579–G585 (1992).

    CAS  PubMed  Google Scholar 

  56. Yamada, Y., Webber, E. M., Kirillova, I., Peschon, J. J. & Fausto, N. Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28, 959–970 (1998).

    CAS  PubMed  Google Scholar 

  57. Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ando, K. et al. Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene 22, 7796–7803 (2003).

    CAS  PubMed  Google Scholar 

  59. Hilliard, V. C., Frey, M. R., Dempsey, P. J., Peek, R. M. Jr & Polk, D. B. TNF-α converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G338–G346 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Anders, R. A., Subudhi, S. K., Wang, J., Pfeffer, K. & Fu, Y. X. Contribution of the lymphotoxin β receptor to liver regeneration. J. Immunol. 175, 1295–1300 (2005).

    CAS  PubMed  Google Scholar 

  61. Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97 (2012).

    CAS  PubMed  Google Scholar 

  62. Kishimoto, T. IL-6: from its discovery to clinical applications. Int. Immunol. 22, 347–352 (2010).

    CAS  PubMed  Google Scholar 

  63. Brandl, K. et al. MyD88 signaling in non-hematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands. Proc. Natl Acad. Sci. USA 107, 19967–19972 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. Makki, N., Thiel, K. W. & Miller, F. J. Jr. The epidermal growth factor receptor and its ligands in cardiovascular disease. Int. J. Mol. Sci. 14, 20597–20613 (2013).

    PubMed  PubMed Central  Google Scholar 

  65. Taniguchi, K. et al. A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015). This key paper describes the role of gp130-induced, Hippo-independent YAP signalling in epithelial regeneration.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nikoopour, E., Bellemore, S. M. & Singh, B. IL-22, cell regeneration and autoimmunity. Cytokine 74, 35–42 (2015).

    CAS  PubMed  Google Scholar 

  67. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).

    CAS  PubMed  Google Scholar 

  68. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zenewicz, L. A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007). This paper is an important account of the unique regenerative function of IL-22.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Radaeva, S., Sun, R., Pan, H. N., Hong, F. & Gao, B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39, 1332–1342 (2004).

    CAS  PubMed  Google Scholar 

  71. Pappu, R., Rutz, S. & Ouyang, W. Regulation of epithelial immunity by IL-17 family cytokines. Trends Immunol. 33, 343–349 (2012).

    CAS  PubMed  Google Scholar 

  72. Hymowitz, S. G. et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J. 20, 5332–5341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ely, L. K., Fischer, S. & Garcia, K. C. Structural basis of receptor sharing by interleukin 17 cytokines. Nature Immunol. 10, 1245–1251 (2009).

    CAS  Google Scholar 

  74. Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).

    CAS  PubMed  Google Scholar 

  75. Song, X. et al. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nature Immunol. 12, 1151–1158 (2011).

    CAS  Google Scholar 

  76. Wang, K. et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Stepniak, E. et al. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 20, 2306–2314 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Sakurai, T., Maeda, S., Chang, L. & Karin, M. Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl Acad. Sci. USA 103, 10544–10551 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chang, L. et al. The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. Cell 124, 601–613 (2006).

    CAS  PubMed  Google Scholar 

  80. Papa, S. et al. Gadd45β promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J. Clin. Invest. 118, 1911–1923 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Schwabe, R. F. & Brenner, D. A. Mechanisms of liver injury. I. TNF-α-induced liver injury: role of IKK, JNK, and ROS pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G583–G589 (2006).

    CAS  PubMed  Google Scholar 

  82. Hasselblatt, P., Rath, M., Komnenovic, V., Zatloukal, K. & Wagner, E. F. Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 17105–17110 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  83. Seki, E., Brenner, D. A. & Karin, M. A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 143, 307–320 (2012).

    CAS  PubMed  Google Scholar 

  84. Jiang, H., Grenley, M. O., Bravo, M. J., Blumhagen, R. Z. & Edgar, B. A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell 8, 84–95 (2011).

    CAS  PubMed  Google Scholar 

  85. Frey, M. R., Golovin, A. & Polk, D. B. Epidermal growth factor-stimulated intestinal epithelial cell migration requires Src family kinase-dependent p38 MAPK signaling. J. Biol. Chem. 279, 44513–44521 (2004).

    CAS  PubMed  Google Scholar 

  86. Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nature Immunol. 12, 715–723 (2011).

    CAS  Google Scholar 

  87. Maeda, S. et al. IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity 19, 725–737 (2003).

    CAS  PubMed  Google Scholar 

  88. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).

    CAS  PubMed  Google Scholar 

  89. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004). This is the first account of the crucial tumour-promoting function of NF-κB signalling in intestinal epithelial cells and macrophages.

    CAS  PubMed  Google Scholar 

  90. Egan, L. J. et al. IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium. Proc. Natl Acad. Sci. USA 101, 2452–2457 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    ADS  CAS  PubMed  Google Scholar 

  92. Eckmann, L. et al. Opposing functions of IKKβ during acute and chronic intestinal inflammation. Proc. Natl Acad. Sci. USA 105, 15058–15063 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).

    CAS  PubMed  Google Scholar 

  94. Jiang, H. & Edgar, B. A. Intestinal stem cell function in Drosophila and mice. Curr. Opin. Genet. Dev. 22, 354–360 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ernst, M., Thiem, S., Nguyen, P. M., Eissmann, M. & Putoczki, T. L. Epithelial gp130/Stat3 functions: an intestinal signaling node in health and disease. Semin. Immunol. 26, 29–37 (2014).

    CAS  PubMed  Google Scholar 

  96. Kolls, J. K., McCray, P. B. Jr & Chan, Y. R. Cytokine-mediated regulation of antimicrobial proteins. Nature Rev. Immunol. 8, 829–835 (2008).

    CAS  Google Scholar 

  97. Wittkopf, N. et al. Activation of intestinal epithelial Stat3 orchestrates tissue defense during gastrointestinal infection. PLoS ONE 10, e0118401 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. Grivennikov, S. I. & Karin, M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21, 11–19 (2010).

    CAS  PubMed  Google Scholar 

  99. Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009).

    CAS  PubMed  Google Scholar 

  100. Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genet. 43, 246–252 (2011).

    CAS  PubMed  Google Scholar 

  101. Moh, A. et al. Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery. Lab. Invest. 87, 1018–1028 (2007).

    CAS  PubMed  Google Scholar 

  102. He, G. et al. Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Johnson, R. & Halder, G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nature Rev. Drug Discov. 13, 63–79 (2014).

    CAS  Google Scholar 

  104. Baddour, L. M., Cha, Y. M. & Wilson, W. R. Clinical practice. Infections of cardiovascular implantable electronic devices. N. Engl. J. Med. 367, 842–849 (2012).

    CAS  PubMed  Google Scholar 

  105. Zhang, J. et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature Cell Biol. 11, 1444–1450 (2009).

    CAS  PubMed  Google Scholar 

  106. Tschaharganeh, D. F. et al. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144, 1530–1542 (2013).

    CAS  PubMed  Google Scholar 

  107. Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes Dev. 27, 355–371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ren, F. et al. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc. Natl Acad. Sci. USA 107, 21064–21069 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147–4158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Staley, B. K. & Irvine, K. D. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr. Biol. 20, 1580–1587 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhou, D. et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc. Natl Acad. Sci. USA 108, e1312–e1320 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Camargo, F. D. et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054–2060 (2007).

    CAS  PubMed  Google Scholar 

  114. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Fre, S. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968 (2005).

    ADS  CAS  PubMed  Google Scholar 

  116. Stanger, B. Z., Datar, R., Murtaugh, L. C. & Melton, D. A. Direct regulation of intestinal fate by Notch. Proc. Natl Acad. Sci. USA 102, 12443–12448 (2005).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  117. van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005). References 115 to 117 describe the crucial role of Notch signalling in the control of stem-cell fate in the mammalian gut.

    ADS  CAS  PubMed  Google Scholar 

  118. Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).

    ADS  CAS  PubMed  Google Scholar 

  119. Cordero, J. B. et al. c-Src drives intestinal regeneration and transformation. EMBO J. 33, 1474–1491 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998).

    CAS  PubMed  Google Scholar 

  121. Liu, S. et al. Lgr4 gene deficiency increases susceptibility and severity of dextran sodium sulfate-induced inflammatory bowel disease in mice. J. Biol. Chem. 288, 8794–8803 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Ashton, G. H. et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev. Cell 19, 259–269 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Miyoshi, H., Ajima, R., Luo, C. T., Yamaguchi, T. P. & Stappenbeck, T. S. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 338, 108–113 (2012). This paper is an important account of the key parts played by Wnt and TGFβ in control of intestinal regeneration.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  124. Clevers, H. C. & Bevins, C. L. Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physiol. 75, 289–311 (2013).

    CAS  PubMed  Google Scholar 

  125. Potten, C. S. Extreme sensitivity of some intestinal crypt cells to X and γ irradiation. Nature 269, 518–521 (1977).

    ADS  CAS  PubMed  Google Scholar 

  126. Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915–920 (2008).

    CAS  PubMed  Google Scholar 

  127. Munoz, J. et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers. EMBO J. 31, 3079–3091 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Roche, K. C. et al. SOX9 maintains reserve stem cells and preserves radio-resistance in mouse small intestine. Gastroenterology 149, 1553–1563 (2015).

    CAS  PubMed  Google Scholar 

  129. Buczacki, S. J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013).

    ADS  CAS  PubMed  Google Scholar 

  130. Choi, T. Y., Ninov, N., Stainier, D. Y. & Shin, D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146, 776–788 (2014).

    CAS  PubMed  Google Scholar 

  131. Grompe, M. Liver stem cells, where art thou? Cell Stem Cell 15, 257–258 (2014).

    CAS  PubMed  Google Scholar 

  132. Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015). This paper shows that periportal hepatocytes rather than oval cells are responsible for liver regeneration after injury, but do not give rise to cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Apte, U. et al. Wnt/β-catenin signaling mediates oval cell response in rodents. Hepatology 47, 288–295 (2008).

    CAS  PubMed  Google Scholar 

  134. Itoh, T., Kamiya, Y., Okabe, M., Tanaka, M. & Miyajima, A. Inducible expression of Wnt genes during adult hepatic stem/progenitor cell response. FEBS Lett. 583, 777–781 (2009).

    CAS  PubMed  Google Scholar 

  135. Yang, W. et al. Wnt/β-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 68, 4287–4295 (2008).

    CAS  PubMed  Google Scholar 

  136. Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  137. Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Med. 18, 572–579 (2012).

    ADS  CAS  PubMed  Google Scholar 

  139. Park, H. W. et al. Alternative Wnt signaling activates YAP/TAZ. Cell 162, 780–794 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Chung, A. S. et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nature Med. 19, 1114–1123 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank H. Gehart for producing the figures. Owing to space limitations, primary findings have been cited through reviews. Work by M.K., who is an American Cancer Society Research Professor and holder of the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases, is supported by the US National Institutes of Health, the Alliance for Lupus Research, the Lymphoma and Leukemia Society and the Superfund Basic Research Program. H.C. is supported by Stand Up to Cancer, the European Research Council, Alpe d'HuZes/KWF and the Netherlands Research Council NWO.

Author information

Authors and Affiliations

  1. Departments of Pharmacology and Pathology, Laboratory of Gene Regulation and Signal Transduction, Moores Cancer Center, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0636, California, USA

    Michael Karin

  2. Princess Máxima Center and Hubrecht Institute, Uppsalalaan 8, Utrecht, 3584 CR, the Netherlands

    Hans Clevers

  3. University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, the Netherlands

    Hans Clevers

Authors
  1. Michael Karin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Clevers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael Karin or Hans Clevers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karin, M., Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016). https://doi.org/10.1038/nature17039

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature17039

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer