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:

Role of TLRs and DAMPs in allograft inflammation and transplant outcomes

Nature Reviews Nephrology volume 12, pages 281–290 (2016)Cite this article

Subjects

Key Points

  • Sterile inflammation occurs in organs after their surgical removal and implantation into a recipient

  • Inflammation that occurs after solid organ transplantation can precipitate acute allograft rejection, impede transplant tolerance and enhance the development of chronic allograft rejection

  • Experimental and clinical studies have shown that several endogenous substances, also known as damage associated molecular patterns contribute to both acute and chronic allograft rejection

  • Toll-like receptors, which are among the best characterized innate immune receptors, induce inflammation and impair outcomes after solid organ transplantation

  • Clinical studies are investigating strategies to inhibit innate immune responses after organ transplantation; approaches to reduce inflammation without compromising host defence to pathogens would substantially improve outcomes for transplant recipients

Abstract

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances — damage-associated molecular patterns (DAMPs) — that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Inflammation initiation and maintenance after organ transplantation.

Similar content being viewed by others

References

  1. Wu, H. & Chadban, S. J. Roles of Toll-like receptors in transplantation. Curr. Opin. Organ Transplant. 19, 1–7 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Mori, D. N., Kreisel, D., Fullerton, J. N., Gilroy, D. W. & Goldstein, D. R. Inflammatory triggers of acute rejection of organ allografts. Immunol. Rev. 258, 132–144 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chong, A. & Alegre, M. The impact of infection and tissue damage in solid-organ transplantation. Nat. Rev. Immunol. 12, 459–471 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McFarland-Mancini, M. M. et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J. Immunol. 184, 7219–7228 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Cameron, G. D. et al. Haptoglobin phenotype correlates with development of cardiac transplant vasculopathy. J. Heart Lung Transplant. 23, 43–49 (2004).

    Article  Google Scholar 

  6. Shirali, A. & Goldstein, D. Tracking the toll of kidney disease. J. Am. Soc. Nephrol. 19, 1444–1450 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Shirali, A. & Goldstein, D. R. Activation of the innate immune system by the endogenous ligand hyaluronan. Curr. Opin. Organ Transplant. 13, 20–25 (2008).

    Article  PubMed  Google Scholar 

  8. Chen, G. Y. & Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gjertson, D. Impact of delayed graft function and acute rejection on kidney graft survival. Clin. Transpl. 467–480 (2000).

  10. Debout, A. et al. Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. Kidney Int. 87, 343–349 (2015).

    Article  PubMed  Google Scholar 

  11. Stehlik, J. et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult heart transplant report — 2011. J. Heart Lung Transplant. 30, 1078–1094 (2011).

    Article  PubMed  Google Scholar 

  12. Lund, L. H. et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult heart transplantation report — focus theme: early graft failure. J. Heart Lung Transplant. 34, 1244–1254 (2015).

    Article  PubMed  Google Scholar 

  13. Chalasani, G. et al. The allograft defines the type of rejection (acute versus chronic) in the face of an established effector immune response. J. Immunol. 172, 7813–7820 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Ponticelli, C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol. Dial. Transplant. 29, 1134–1140 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Matas, A. J. et al. 2202 kidney transplant recipients with 10 years of graft function: what happens next? Am. J. Trans. 8, 2410–2419 (2008).

    Article  CAS  Google Scholar 

  16. Floerchinger, B. et al. Inflammatory immune responses in a reproducible mouse brain death model. Transpl. Immunol. 27, 25–29 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Hoffmann, S. C. et al. Molecular and immunohistochemical characterization of the onset and resolution of human renal allograft ischemia-reperfusion injury. Transplantation 74, 916–923 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Sheen, J. H. & Heeger, P. S. Effects of complement activation on allograft injury. Curr. Opin. Organ Transplant. 20, 468–475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ali, F., Dua, A. & Cronin, D. C. Changing paradigms in organ preservation and resuscitation. Curr. Opin. Organ Transplant. 20, 152–158 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Li, W. et al. Intravital 2-photon imaging of leukocyte trafficking in beating heart. J. Clin. Invest. 122, 2499–2508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pittman, K. & Kubes, P. Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun. 5, 315–323 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhuang, Q. & Lakkis, F. G. Dendritic cells and innate immunity in kidney transplantation. Kidney Int. 5, 315–3 (2015).

    Google Scholar 

  23. Lakkis, F. G. Where is the alloimmune response initiated? Am. J. Transplant 3, 241–242 (2003).

    Article  PubMed  Google Scholar 

  24. Tsung, A. et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J. Exp. Med. 201, 1135–1143 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, H. et al. HMGB1 contributes to kidney ischemia reperfusion injury. J. Am. Soc. Nephrol. 21, 1878–1890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rabadi, M. M., Ghaly, T., Goligorksy, M. S. & Ratliff, B. B. HMGB1 in renal ischemic injury. Am. J. Physiol. Renal Physiol. 303, F873–F885 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kamo, N. et al. ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury. Hepatology 58, 351–362 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Tsung, A. et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4-dependent reactive oxygen species production and calcium-mediated signaling. J. Exp. Med. 204, 2913–2923 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Helena Erlandsson Harris, U. A. Mini-review: the nuclear protein HMGB1 as a proinflammatory mediator. Eur. J. Immunol. 34, 1503–1512 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, A. et al. Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury. Transpl. Int. 27, 1077–1085 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Syrjälä, S. O. et al. Increased Th17 rather than Th1 alloimmune response is associated with cardiac allograft vasculopathy after hypothermic preservation in the rat. J. Heart Lung Transplant. 29, 1047–1057 (2010).

    Article  PubMed  Google Scholar 

  32. Huang, Y. et al. Extracellular hmgb1 functions as an innate immune-mediator implicated in murine cardiac allograft acute rejection. Am. J. Transplant. 7, 799–808 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Moser, B. et al. Blockade of RAGE suppresses alloimmune reactions in vitro and delays allograft rejection in murine heart transplantation. Am. J. Transplant. 7, 293–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Dessing, M. C. et al. RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury. J. Innate Immun. 4, 80–85 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Li, J. H. et al. Blockade of extracellular HMGB1 suppresses xenoreactive B cell responses and delays acute vascular xenogeneic rejection. Am. J. Transplant. 15, 2062–2074 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Zou, H. et al. HMGB1 is involved in chronic rejection of cardiac allograft via promoting inflammatory-like mDCs. Am. J. Transplant. 14, 1765–1777 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Hausenloy, D. J. & Yellon, D. M. Ischaemic conditioning and reperfusion injury. Nat. Rev. Cardiol. http://dx.doi.org/10.1038/nrcardio.2016.5 (2016).

  38. Wu, H. et al. Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia-reperfusion injury in mice. Kidney Int. 85, 824–832 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Netea, Mihai, G., Quintin, J. & van der Meer, Jos, W. M. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11, 1173–1179 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Teder, P. et al. Resolution of lung inflammation by CD44. Science 296, 155–158 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Noble, P. W., McKee, C. M., Cowman, M. & Shin, H. S. Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages. J. Exp. Med. 183, 2373–2378 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Rouschop, K. M. A. et al. Protection against renal ischemia reperfusion injury by CD44 disruption. J. Am. Soc. Nephrol. 16, 2034–2043 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Wu, H. et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117, 2847–2859 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Bollyky, P. L. et al. Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J. Immmunol. 179, 744–747 (2007).

    Article  CAS  Google Scholar 

  47. Muto, J. et al. Hyaluronan digestion controls DC migration from the skin. J. Clin. Invest. 124, 1309–1319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wells, A. et al. Increased hyaluronan in acutely rejecting human kidney grafts. Transplantation 55, 1346–1349 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Tesar, B. M. et al. The role of hyaluronan degradation products as innate alloimmune agonists. Am. J. Transplant. 6, 2622–2635 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Todd, J. L. et al. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. Am. J. Respir. Crit. Care Med. 189, 556–566 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kono, H., Chen, C.-J., Ontiveros, F. & Rock, K. L. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J. Clin. Invest. 120, 1939–1949 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shen, H., Kreisel, D. & Goldstein, D. R. Processes of sterile inflammation. J. Immunol. 191, 2857–2863 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Oh, K.-H. et al. Targeted gene disruption of the heat shock protein 72 gene (hsp70.1) in the donor tissue is associated with a prolonged rejection-free survival in the murine skin allograft model. Transplant Immunol. 13, 273–281 (2004).

    Article  CAS  Google Scholar 

  54. Tesar, B. & Goldstein, D. R. Acute allograft rejections occurs independently of inducible HSP-70. Transplantation 11, 1513–1517 (2007).

    Article  CAS  Google Scholar 

  55. Quaye, I. K. Haptoglobin, inflammation and disease. Trans. R. Soc. Trop. Med. Hyg. 102, 735–742 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Shen, H. et al. Haptoglobin activates innate immunity to enhance acute transplant rejection in mice. J. Clin. Invest. 122, 383–387 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Goldstein, D. R., Tesar, B. M., Akira, S. & Lakkis, F. G. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J. Clin. Invest. 111, 1571–1578 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shen, H. et al. Haptoglobin enhances cardiac transplant rejection. Circ. Res. 116, 1670–1679 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brubaker, S. W., Bonham, K. S., Zanoni, I. & Kagan, J. C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 33, 257–290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yoneyama, M., Onomoto, K., Jogi, M., Akaboshi, T. & Fujita, T. Viral RNA detection by RIG-I-like receptors. Curr. Opin. Immunol. 32, 48–53 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Fitzgerald, M. E., Rawling, D. C., Vela, A. & Pyle, A. M. An evolving arsenal: viral RNA detection by RIG-I-like receptors. Curr. Opin. Microbiol. 20, 76–81 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Seto, T. et al. Upregulation of the apoptosis-related inflammasome in cardiac allograft rejection. J. Heart Lung Transplant. 29, 352–359 (2010).

    Article  PubMed  Google Scholar 

  64. Shah, K. B., Mauro, A. G., Flattery, M., Toldo, S. & Abbate, A. Formation of the inflammasome during cardiac allograft rejection. Int. J. Cardiol. 201, 328–330 (2015).

    Article  PubMed  Google Scholar 

  65. Pandey, S., Kawai, T. & Akira, S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 7, a016246 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  66. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Crellin, N. K. et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Leemans, J. C. et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115, 2894–2903 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Patole, P. S. et al. Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney Int. 68, 2582–2587 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Leventhal, J. S. & Schroppel, B. Toll-like receptors in transplantation: sensing and reacting to injury. Kidney Int. 81, 826–832 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Tesar, B. M., Zhang, J., Li, Q. & Goldstein, D. R. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88, a toll like receptor signal adaptor protein. Am. J. Transplant. 4, 1429–1439 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Walker, W. E. et al. Absence of innate MyD88 signaling promotes inducible allograft acceptance. J. Immunol. 177, 5307–5316 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Wu, H. et al. Absence of MyD88 signaling induces donor-specific kidney allograft tolerance. J. Am. Soc. Nephrol. 23, 1701–1716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kruger, B. et al. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc. Natl Acad. Sci. USA 106, 3390–3395 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Pulskens, W. P. et al. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS ONE 3, e3596 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Oberbarnscheidt, M. H. et al. Non-self recognition by monocytes initiates allograft rejection. J. Clin. Invest. 124, 3579–3589 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen, L. et al. TLR engagement prevents transplantation tolerance. Am. J. Trans. 6, 2282–2291 (2006).

    Article  CAS  Google Scholar 

  78. Zhang, X. et al. Induction of alloimmune tolerance in heart transplantation through gene silencing of TLR adaptors. Am. J. Trans. 12, 2675–2688 (2012).

    Article  CAS  Google Scholar 

  79. Kaczorowski, D. J. et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation 87, 1455–1463 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang, S. et al. Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis. Model. Mech. 3, 92–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Thierry, A. et al. The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33. PLoS ONE 9, e88742 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ilmakunnas, M. et al. High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation. Liver Transplant. 14, 1517–1525 (2008).

    Article  Google Scholar 

  83. Cantu, E. et al. Gene set enrichment analysis identifies key innate immune pathways in primary graft dysfunction after lung transplantation. Am. J. Trans. 13, 1898–1904 (2013).

    Article  CAS  Google Scholar 

  84. Andrade, C. F. et al. Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J. Heart Lung Transplant. 25, 1317–1323 (2006).

    Article  PubMed  Google Scholar 

  85. Palmer, S. M. et al. Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin. Transplant. 20, 30–36 (2006).

    Article  PubMed  Google Scholar 

  86. Dhillon, N. et al. A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. J. Hepatol. 53, 67–72 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Dessing, M. C. et al. Intragraft Toll-like receptor profiling in acute renal allograft rejection. Nephrol. Dial. Transplant. 25, 4087–4092 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Dessing, M. C. et al. Toll-like receptor family polymorphisms are associated with primary renal diseases but not with renal outcomes following kidney transplantation. PLoS ONE 10, e0139769 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kuhlicke, J., Frick, J. S., Morote-Garcia, J. C., Rosenberger, P. & Eltzschig, H. K. Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS ONE 2, e1364 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Powers, K. A. et al. Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages. J. Exp. Med. 203, 1951–1961 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zarember, K. A. & Godowski, P. J. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J. Immunol. 168, 554–561 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Calfee, C. S. et al. Plasma receptor for advanced glycation end-products predicts duration of ICU stay and mechanical ventilation in patients after lung transplantation. J. Heart Lung Transplant. 26, 675–680 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Oetting, W. S. et al. Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients. Liver Transpl. 18, 1399–1405 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kastelijn, E. A. et al. Polymorphisms in innate immunity genes associated with development of bronchiolitis obliterans after lung transplantation. J. Heart Lung Transplant. 29, 665–671 (2010).

    Article  PubMed  Google Scholar 

  95. Ducloux, D. et al. Relevance of Toll-like receptor-4 polymorphisms in renal transplantation. Kidney Int. 67, 2454–2461 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Palmer, C., Diehn, M., Alizadeh, A. A. & Brown, P. O. Cell-type specific gene expression profiles of leukocytes in human peripheral blood. BMC Genomics 7, 115–115 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Park, W. D., Griffin, M. D., Cornell, L. D., Cosio, F. G. & Stegall, M. D. Fibrosis with inflammation at one year predicts transplant functional decline. J. Am. Soc. Nephrol. 21, 1987–1997 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Park, W., Griffin, M., Grande, J. P., Cosio, F. & Stegall, M. D. Molecular evidence of injury and inflammation in normal and fibrotic renal allografts one year posttransplant. Transplantation 83, 1466–1476 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Braudeau, C. et al. Contrasted blood and intragraft toll-like receptor 4 mRNA profiles in operational tolerance versus chronic rejection in kidney transplant recipients. Transplantation 86, 130–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Methe, H., Zimmer, E., Grimm, C., Nabauer, M. & Koglin, J. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation. Transplantation 78, 1324–1331 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Naesens, M. et al. Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. Kidney Int. 80, 1364–1376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Khatri, P. et al. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. J. Exp. Med. 210, 2205–2221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Saito, T. et al. Distinct expression patterns of alveolar “alarmins” in subtypes of chronic lung allograft dysfunction. Am. J. Trans. 14, 1425–1432 (2014).

    Article  CAS  Google Scholar 

  104. Chan, J. K. et al. Alarmins: awaiting a clinical response. J. Clin. Invest. 122, 2711–2719 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Eikmans, M. et al. Expression of surfactant protein-C, S100A8, S100A9, and B cell markers in renal allografts: investigation of the prognostic value. J. Soc. Am. Neprol 16, 3771–3786 (2005).

    Article  CAS  Google Scholar 

  106. Dessing, M. C. et al. The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion. Kidney Int. 87, 85–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Shimizu, K. et al. Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection. Circulation 124, 2920–2932 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  109. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  110. Soares, M. P., Gozzelino, R. & Weis, S. Tissue damage control in disease tolerance. Trends Immunol. 35, 483–494 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Anders, H.-J. Immune system modulation of kidney regeneration[mdash]mechanisms and implications. Nat. Rev. Nephrol. 10, 347–358 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Serhan, C. N., Chiang, N. & Van Dyke, T. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8, 349–361 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kim, M.-G. et al. The heat-shock protein-70-induced renoprotective effect is partially mediated by CD4+CD25+Foxp3+ regulatory T cells in ischemia/reperfusion-induced acute kidney injury. Kidney Int. 85, 62–71 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Weidemann, A. & Johnson, R. S. Biology of HIF-1α. Cell Death Differ. 15, 621–627 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Kido, M. et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J. Am. College Cardiol. 46, 2116–2124 (2005).

    Article  CAS  Google Scholar 

  116. Cai, Z. et al. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1α. Cardiovasc. Res. 77, 463–470 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion — from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chen, Y. et al. Remote ischemic preconditioning fails to improve early renal function of patients undergoing living-donor renal transplantation: a randomized controlled trial. Transplantation 95, e4–6 (2013).

    Article  PubMed  Google Scholar 

  120. Hill, P. et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 19, 39–46 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ferenbach, D. A. et al. The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney Int. 79, 966–976 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  123. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  124. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  125. Medzhitov, R. & Janeway, C. Jr. Innate immunity. N. Engl. J. Med. 343, 338–344 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

D.R.G.'s work is supported by NIH/NIA grant R01AG028082, S.J.C.'s work is supported by NHMRC Project Grant funding and S.B.'s work is supported by the CENTAURE foundation, the IHU-Cesti project, the French National Research Agency, and the Nantes Metropole and the Pays de la Loire Region.

Author information

Authors and Affiliations

  1. Instituto Gulbenkian de Ciência, Rua da Quinta Grande, Oeiras, 2780–156, Portugal

    Faouzi Braza

  2. INSERM, UMR 1064, CHU de Nantes, ITUN, 30 Bd Jean Monnet, Nantes, F-44093, France

    Sophie Brouard

  3. Renal Medicine and Transplantation, Royal Prince Alfred Hospital, Missenden Road Camperdown, Sydney, 2050, NSW, Australia

    Steve Chadban

  4. Kidney Node, Charles Perkins Centre, University of Sydney, Missenden Road, Camperdown, 2093, NSW, Australia

    Steve Chadban

  5. Department of Internal Medicine, 333 Cedar St, Yale School of Medicine, New Haven, 06525, Connecticut, USA

    Daniel R. Goldstein

  6. Department of Immunobiology, 300 Cedar St, Yale School of Medicine, New Haven, 06525, Connecticut, USA

    Daniel R. Goldstein

Authors
  1. Faouzi Braza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sophie Brouard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steve Chadban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel R. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data, discussed the content, wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Daniel R. Goldstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Sterile inflammation

Inflammation that occurs following the necrosis- mediated release of activators of inflammation in medical conditions such as ischaemia–reperfusion injury, crystalline-induced arthritis, acute lung injury and chronic inflammatory conditions, without an identifiable infectious precipitant.

Bronchiolitis obliterans syndrome

A manifestation of chronic allograft rejection characterized by a decline in pulmonary function that affects more than half of lung recipients 5 years after transplantation and accounts for a considerable proportion of lung allograft losses and recipient deaths.

Operationally tolerant recipients

Subgroup of patients who spontaneously tolerate their graft and maintain allograft function without the use of immunosuppressants for at least 1 year, in the absence of deleterious responses.

Restrictive allograft syndrome

Newly described phenotype of chronic lung allograft dysfunction characterized by a persistentdecline in vital and total lung capacities and allograft parenchymal fibrosis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Braza, F., Brouard, S., Chadban, S. et al. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 12, 281–290 (2016). https://doi.org/10.1038/nrneph.2016.41

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2016.41

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing