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:

Sterile inflammation: sensing and reacting to damage

Key Points

  • Sterile inflammation occurs in the absence of microorganisms and is typically associated with the recognition of intracellular contents released from damaged and necrotic cells (also known as damage-associated molecular patterns) by inflammatory signalling receptors. Sterile inflammation can also be induced by exogenous material, such as silica and asbestos particles, which can injure cells.

  • Host receptors used in microbial detection, specifically pattern recognition receptors such as the Toll-like receptors (TLRs) and NOD-like recpetors (NLRs), are also activated by endogenous and non-infectious stimuli and mediate sterile inflammatory responses. However, host receptors that are not necessarily involved in pathogen recognition, such as receptor for advanced glycation end products (RAGE), can also sense sterile stimuli.

  • NLRP3 (NOD-, LRR- and pyrin domain-containing 3) is a member of the NLR family of receptors involved in innate immunity and has the ability to sense numerous structurally diverse stimuli. The mechanism by which NLRP3 achieves this is still not completely understood, but it may involve the sensing of reactive oxygen species, ionic changes within the cell or lysosomal membrane damage.

  • Intracellular cytokines, such as interleukin-1α (IL-1α), are also important mediators of the sterile inflammatory response and can be released in their biologically active forms from necrotic cells.

  • Sterile inflammation has been associated with certain disease states, such as the increased tissue damage that results from ischaemia–reperfusion in myocardial infarction, as well as atherosclerosis, silicosis and Alzheimer's disease. Furthermore, sterile inflammation may also have an important role in host immune responses against tumours.

Abstract

Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.

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

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

Figure 1: Mechanisms for inducing sterile inflammation.
Figure 2: Proposed pathways for NLRP3 activation.
Figure 3: Model for IL-1-mediated neutrophil recruitment in response to necrotic cell death.

Similar content being viewed by others

References

  1. Mossman, B. T. & Churg, A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am. J. Respir. Crit. Care Med. 157, 1666–1680 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Cotran, R. S., Kumar, V. & Robbins, S. in Robbins Pathologic Basis of Disease (ed. Schoen, F. J.) 6–11 (W. B. Saunders Company, Philadelphia, 1994).

    Google Scholar 

  3. Cotran, R. S., Kumar, V. & Robbins, S . in Robbins Pathologic Basis of Disease (ed. Schoen, F. J.) 1255–1259 (W. B. Saunders Company, Philadelphia, 1994).

    Google Scholar 

  4. Weiner, H. L. & Frenkel, D. Immunology and immunotherapy of Alzheimer's disease. Nature Rev. Immunol. 6, 404–416 (2006).

    Article  CAS  Google Scholar 

  5. Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nature Immunol. 11, 997–1004 (2010).

    Article  CAS  Google Scholar 

  9. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Quintana, F. J. & Cohen, I. R. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J. Immunol. 175, 2777–2782 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Bours, M. J., Swennen, E. L., Di Virgilio, F., Cronstein, B. N. & Dagnelie, P. C. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Babelova, A. et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via Toll-like and P2X receptors. J. Biol. Chem. 284, 24035–24048 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Eigenbrod, T., Park, J. H., Harder, J., Iwakura, Y. & Nunez, G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells. J. Immunol. 181, 8194–8198 (2008). This paper shows that the passive release of IL-1α from necrotic cells, in particular necrotic dendritic cells, is important for the recruitment of neutrophils in the sterile inflammatory response through the production of CXCL1 by cells responsive to IL-1α.

    Article  CAS  PubMed  Google Scholar 

  16. Moussion, C., Ortega, N. & Girard, J. P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One 3, e3331 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008).

    Article  CAS  Google Scholar 

  18. Basu, S., Binder, R. J., Suto, R., Anderson, K. M. & Srivastava, P. K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. Int. Immunol. 12, 1539–1546 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Hofmann, M. A. et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889–901 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007). This paper demonstrates a crucial role for IL-1α in sterile inflammation and, in particular, neutrophil recruitment induced by necrotic cells.

    Article  CAS  PubMed  Google Scholar 

  23. Mbitikon-Kobo, F. M. et al. Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions. J. Immunol. 182, 3846–3854 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Weber, A. N. et al. Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Nature Immunol. 4, 794–800 (2003).

    Article  CAS  Google Scholar 

  25. Vabulas, R. M. et al. Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276, 31332–31339 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Yu, M. et al. HMGB1 signals through Toll-like receptor (TLR) 4 and TLR2. Shock 26, 174–179 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Liu-Bryan, R., Scott, P., Sydlaske, A., Rose, D. M. & Terkeltaub, R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 52, 2936–2946 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Gao, B. & Tsan, M. F. Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J. Biol. Chem. 278, 174–179 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Rouhiainen, A., Tumova, S., Valmu, L., Kalkkinen, N. & Rauvala, H. Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J. Leukoc. Biol. 81, 49–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Youn, J. H., Oh, Y. J., Kim, E. S., Choi, J. E. & Shin, J. S. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-α production in human monocytes. J. Immunol. 180, 5067–5074 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11, 1173–1179 (2005). This paper shows the dual role of TLRs in mediating sterile inflammation in response to hyaluronan fragments released during injury and in promoting tissue repair.

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Schaefer, L. et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J. Clin. Invest. 115, 2223–2233 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mullick, A. E., Tobias, P. S. & Curtiss, L. K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Michelsen, K. S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679–10684 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cavassani, K. A. et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J. Exp. Med. 205, 2609–2621 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Imaeda, A. B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kono, H., Karmarkar, D., Iwakura, Y. & Rock, K. L. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J. Immunol. 184, 4470–4478 (2010). This study shows the crucial role for macrophages in mediating the inflammatory response to sterile cell death, such as by IL-1α production.

    Article  CAS  PubMed  Google Scholar 

  42. Wang, X., Feuerstein, G. Z., Gu, J. L., Lysko, P. G. & Yue, T. L. Interleukin-1β induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis 115, 89–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Gabay, C., Lamacchia, C. & Palmer, G. IL-1 pathways in inflammation and human diseases. Nature Rev. Rheumatol. 6, 232–241 (2010).

    Article  CAS  Google Scholar 

  44. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008). This study was pivotal in providing a model of NLRP3 activation that involves lysosomal damage and cathepsin B activation.

    Article  CAS  Google Scholar 

  45. Raines, E. W., Dower, S. K. & Ross, R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science 243, 393–396 (1989).

    Article  CAS  PubMed  Google Scholar 

  46. Boni-Schnetzler, M. et al. Increased interleukin (IL)-1β messenger ribonucleic acid expression in β-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunol. 10, 266–272 (2009).

    Article  CAS  Google Scholar 

  49. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fernandes-Alnemri, T. et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nature Immunol. 11, 385–393 (2010).

    Article  CAS  Google Scholar 

  52. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010).

    Article  CAS  Google Scholar 

  53. Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Franchi, L., Eigenbrod, T. & Nunez, G. Cutting edge: TNF-α mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J. Immunol. 183, 792–796 (2009). References 53 and 54 provide evidence that the first signal, or priming event, necessary for activation of the NLRP3 inflammasome involves upregulation of NLRP3 expression by NF-κB through the action of TLRs or pro-inflammatory cytokines such as TNF.

    Article  CAS  PubMed  Google Scholar 

  55. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This study is one of the first to identify an endogenous, non-microbial signal for NLPR3 inflammasome activation that can lead to a non-infectious inflammatory disease (in this case, gout).

    Article  CAS  PubMed  Google Scholar 

  56. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).

    Article  CAS  Google Scholar 

  57. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008). This study led to the model of NLRP3 activation that is dependent on the sensing of ROS, and demonstrated a role for NLRP3 in asbestosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010).

    Article  CAS  Google Scholar 

  62. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010).

    Article  CAS  Google Scholar 

  63. el-Moatassim, C. & Dubyak, G. R. A novel pathway for the activation of phospholipase D by P2z purinergic receptors in BAC1.2F5 macrophages. J. Biol. Chem. 267, 23664–23673 (1992).

    CAS  PubMed  Google Scholar 

  64. Pelegrin, P. & Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071–5082 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Locovei, S., Wang, J. & Dahl, G. Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett. 580, 239–244 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Dostert, C. et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 4, e6510 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fubini, B. & Hubbard, A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic. Biol. Med. 34, 1507–1516 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Cruz, C. M. et al. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem. 282, 2871–2879 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Geijtenbeek, T. B. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nature Rev. Immunol. 9, 465–479 (2009).

    Article  CAS  Google Scholar 

  71. Figdor, C. G., van Kooyk, Y. & Adema, G. J. C-type lectin receptors on dendritic cells and Langerhans cells. Nature Rev. Immunol. 2, 77–84 (2002).

    Article  CAS  Google Scholar 

  72. Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunol. 9, 1179–1188 (2008).

    Article  CAS  Google Scholar 

  73. Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Nakamura, N. et al. Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients. DNA Res. 13, 169–183 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009). This paper showed a role for CLEC9A in regulating immune responses to sterile cell death, specifically through the cross-presentation of dead cell-associated antigens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rao, D. A. et al. Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection. J. Exp. Med. 205, 3145–3158 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cohen, I. et al. Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl Acad. Sci. USA 107, 2574–2579 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dinarello, C. A. IL-1: discoveries, controversies and future directions. Eur. J. Immunol. 40, 599–606 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  81. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme. Science 267, 2000–2003 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Fantuzzi, G. et al. Response to local inflammation of IL-1β-converting enzyme-deficient mice. J. Immunol. 158, 1818–1824 (1997).

    CAS  PubMed  Google Scholar 

  84. Mayer-Barber, K. D. et al. Caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J. Immunol. 184, 3326–3330 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Verri, W. A. Jr et al. IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann. Rheum. Dis. 69, 1697–1703 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Fang, F. et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 24, 1043–1055 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R. & Coyle, A. J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28, 367–388 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Shang, L. et al. RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3β signaling pathways. PLoS One 5, e10092 (2010).

    Article  CAS  Google Scholar 

  92. Bucciarelli, L. G. et al. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell. Mol. Life Sci. 59, 1117–1128 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Hori, O. et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270, 25752–25761 (1995).

    Article  CAS  PubMed  Google Scholar 

  94. Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Huang, J. S. et al. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J. Cell Biochem. 81, 102–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Dukic-Stefanovic, S., Schinzel, R., Riederer, P. & Munch, G. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2, 19–34 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Ishihara, K., Tsutsumi, K., Kawane, S., Nakajima, M. & Kasaoka, T. The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett. 550, 107–113 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007).

    Article  CAS  Google Scholar 

  99. Ueno, H. et al. Receptor for advanced glycation end-products (RAGE) regulation of adiposity and adiponectin is associated with atherogenesis in apoE-deficient mouse. Atherosclerosis 211, 431–436 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Soro-Paavonen, A. et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57, 2461–2469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Harja, E. et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J. Clin. Invest. 118, 183–194 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Taylor, K. R. et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J. Biol. Chem. 282, 18265–18275 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155–161 (2010).

    Article  CAS  Google Scholar 

  106. Chen, G. Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Liu, Y., Chen, G. Y. & Zheng, P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol. 30, 557–561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Larsen, C. M. et al. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 32, 1663–1668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pantschenko, A. G. et al. The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression. Int. J. Oncol. 23, 269–284 (2003).

    CAS  PubMed  Google Scholar 

  112. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Brown, S. L. et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 117, 258–269 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007). This paper showed the importance of TLR4 signalling in response to DAMPs derived from tumour cell death after chemotherapy or radiation treatment during the induction of host immune responses that are important for inhibiting tumour growth.

    Article  CAS  PubMed  Google Scholar 

  116. Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. DiPietro, L. A. Wound healing: the role of the macrophage and other immune cells. Shock 4, 233–240 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Kroemer, G . et al. Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 16, 3–11 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Silva, M. T., do Vale, A. & dos Santos, N. M. Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis 13, 463–482 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Miwa, K. et al. Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand. Nature Med. 4, 1287–1292 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Marina-Garcia, N. et al. Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. J. Immunol. 180, 4050–4057 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Basu, S., Binder, R. J., Ramalingam, T. & Srivastava, P. K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14, 303–313 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Kariko, K., Ni, H., Capodici, J., Lamphier, M. & Weissman, D. mRNA is an endogenous ligand for Toll-like receptor 3. J. Biol. Chem. 279, 12542–12550 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Johnson, G. B., Brunn, G. J., Kodaira, Y. & Platt, J. L. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J. Immunol. 168, 5233–5239 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to our colleagues whose work was not cited or was cited through others' review articles because of space limitations. Work in the authors' laboratories is supported by US National Institutes of Health grants CA133185 (G.C.), and DK61707, AR051790, AI06331, AR059688 and DK091191 (G.N.).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Gabriel Nuñez's homepage

Glossary

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow further enhances inflammation, which exacerbates tissue damage.

Reactive oxygen species

(ROS). Oxygen radicals that are mainly produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

Myocardial infarction

An episode of acute cardiac ischaemia that leads to death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.

Atherosclerosis

A chronic disorder of the arterial wall characterized by endothelial cell damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.

Necrosis

A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and the release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self antigens that are released by necrosis can become immunogenic.

Apoptosis

A common form of cell death that is defined by specific morphological changes and by the involvement of caspases. The morphological features include chromatin condensation, plasma membrane blebbing and DNA fragmentation into segments of 180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by neighbouring cells.

High-mobility group box 1

(HMGB1; also known as amphoterin). A nuclear protein that binds DNA in a non-sequence-specific manner and modulates transcription and chromatin remodelling by bending DNA and facilitating the binding of transcription factors and nucleosomes, respectively.

Adjuvant

A substance that stimulates the immune system to enhance the immunogenicity of antigens or vaccines and enhance antigen-specific antibody production.

Inflammasome

A multiprotein complex that contains a pattern recognition receptor (PRR), typically a member of the NOD-like receptor (NLR) family, that, on sensing its cognate agonist, oligomerizes and recruits the adaptor protein ASC (apoptosis-related speck-like protein containing a CARD) through protein domain interactions. ASC can recruit caspase 1 through its CARD, thereby linking the PRR to caspase 1 activation and interleukin-1 production. There are currently four characterized inflammasomes, named by the PRRs that form them: the NRLP1 (NOD-, LRR- and pyrin domain-containing 1), NLRP3, NLRC4 (NOD-, LRR- and CARD-containing 4) and absence in melanoma 2 (AIM2) inflammasomes.

NADPH oxidase

An enzyme system that consists of several cytoplasmic and membrane-bound subunits. The complex is assembled in activated phagocytic cells mainly on phagolysosomal membranes. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid, a highly toxic and microbicidal agent.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, G., Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10, 826–837 (2010). https://doi.org/10.1038/nri2873

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2873

This article is cited by

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