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:

How dying cells alert the immune system to danger

Key Points

  • A large number of pathological processes can damage cells in ways that lead to the common end result of cell death. Therefore, when non-physiological cell death occurs in vivo, it indicates that a potentially dangerous situation is developing in a host.

  • The innate immune system has evolved mechanisms to identify potential danger by detecting abnormal cell death. This is accomplished by sensing the release of a subset of molecules (damage-associated molecular patterns, DAMPs) that are normally hidden in living cells or their local environment but are released or exposed when cells die and lose integrity of their plasma membrane.

  • Upon detecting the presence of DAMPs, the innate immune system initiates an acute inflammatory response that rapidly delivers soluble and cellular defences to the site of damage. This response is a double-edged sword that can contain and repair the damage but can also damage normal tissues and in so doing cause disease.

  • DAMPs also stimulate antigen-presenting cells of the innate immune system to migrate to lymphoid tissues and become immunostimulatory for T cells. In this way, the innate immune response alerts the adaptive immune system to potential danger in a manner that helps to initiate responses to any immunogenic antigens at the site of damage. This might have an important role in initiating T-cell responses to tumours, to transplants and in autoimmunity.

  • There has been recent progress in identifying some of what are probably many DAMPs. There remains much to be learned about these molecules, the cells and receptors that sense them, and the pathways they stimulate.

Abstract

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes — that is, it is part of normal physiological processes — then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Stranger and danger models.
Figure 2: Discriminating between viable cells, necrosis and apoptosis.
Figure 3: Cell death and inflammation.

Similar content being viewed by others

References

  1. Dresser, D. W. Effectiveness of lipid and lipidophilic substances as adjuvants. Nature 191, 1169–1171 (1961).

    Article  CAS  PubMed  Google Scholar 

  2. Dresser, D. W. Specific inhibition of antibody production. II. Paralysis induced in adult mice by small quantities of protein antigen. Immunology 5, 378–388 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54 (Pt 1), 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Meylan, E., Tschopp, J. & Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Kawai, T. & Akira, S. Antiviral signaling through pattern recognition receptors. J. Biochem. (Tokyo) 141, 137–145 (2007).

    Article  CAS  Google Scholar 

  7. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994). This paper introduces the danger model and describes the hypothesis that the recognition of tissue damage is crucial for the activation of antigen-presenting cells and adaptive immune responses.

    Article  CAS  PubMed  Google Scholar 

  8. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nature Rev. Immunol. 4, 469–478 (2004).

    Article  CAS  Google Scholar 

  9. Rock, K. L., Hearn, A., Chen, C. J. & Shi, Y. Natural endogenous adjuvants. Springer Semin. Immunopathol. 26, 231–246 (2005).

    Article  PubMed  Google Scholar 

  10. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nature Med. 5, 1249–1255 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Shi, Y., Zheng, W. & Rock, K. L. Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl Acad. Sci. USA 97, 14590–14595 (2000). References 10 and 11 identified the existence of endogenous molecules (danger signals) that function as adjuvants to promote acquired immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shi, Y. & Rock, K. L. Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens. Eur. J. Immunol. 32, 155–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Mathis, D., Vence, L. & Benoist, C. β-cell death during progression to diabetes. Nature 414, 792–798 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological β-cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Like, A. A. & Rossini, A. A. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193, 415–417 (1976).

    Article  CAS  PubMed  Google Scholar 

  16. Damico, F. M., Kiss, S. & Young, L. H. Sympathetic ophthalmia. Semin. Ophthalmol. 20, 191–197 (2005).

    Article  PubMed  Google Scholar 

  17. Dressler, W. A post-myocardial infarction syndrome; preliminary report of a complication resembling idiopathic, recurrent, benign pericarditis. J. Am. Med. Assoc. 160, 1379–1383 (1956).

    Article  CAS  PubMed  Google Scholar 

  18. Nowak, A. K. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J. Immunol. 170, 4905–4913 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Kouwenhoven, E. A., de Bruin, R. W., Bajema, I. M., Marquet, R. L. & Ijzermans, J. N. Cold ischemia augments allogeneic-mediated injury in rat kidney allografts. Kidney Int. 59, 1142–1148 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Shi, Y., Galusha, S. A. & Rock, K. L. Cutting edge: elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J. Immunol. 176, 3905–3908 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Hu, D. E., Moore, A. M., Thomsen, L. L. & Brindle, K. M. Uric acid promotes tumor immune rejection. Cancer Res. 64, 5059–5062 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Udono, H. & Srivastava, P. K. Heat shock protein 70-associated peptides elicit specific cancer immunity. J. Exp. Med. 178, 1391–1396 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Feng, H., Zeng, Y., Graner, M. W., Likhacheva, A. & Katsanis, E. Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity. Blood 101, 245–252 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. Binder, R. J., Anderson, K. M., Basu, S. & Srivastava, P. K. Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J. Immunol. 165, 6029–6035 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Bausinger, H. et al. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32, 3708–3713 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. 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). This paper identified uric acid as an endogenous adjuvant.

    Article  CAS  PubMed  Google Scholar 

  28. Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Rev. Immunol. 5, 331–342 (2005).

    Article  CAS  Google Scholar 

  29. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002). This paper showed that HMGB1 is released from necrotic but not apoptotic cells and that it induces inflammatory responses in vivo.

    Article  CAS  PubMed  Google Scholar 

  30. Rovere-Querini, P. et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 5, 825–830 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 provides evidence that HMGB1 is an endogenous adjuvant that contributes to tumour immunity in chemotherapy- and radiotherapy-induced cell death.

    Article  CAS  PubMed  Google Scholar 

  32. Ishii, K. J. et al. Genomic DNA released by dying cells induces the maturation of APCs. J. Immunol. 167, 2602–2607 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Bird, A. P., Taggart, M. H., Nicholls, R. D. & Higgs, D. R. Non-methylated CpG-rich islands at the human α-globin locus: implications for evolution of the α-globin pseudogene. EMBO J. 6, 999–1004 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Majno, G., La Gattuta, M. & Thompson, T. E. Cellular death and necrosis: chemical, physical and morphologic changes in rat liver. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 333, 421–465 (1960). This paper provides a detailed description of inflammatory responses to necrotic tissue in vivo.

    Article  CAS  PubMed  Google Scholar 

  35. 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 shows that the IL-1α–IL-1-receptor–MYD88 pathway has an important role in the acute neutrophilic inflammatory response to cell death, whereas Toll-like receptors have only a minor role in this response.

    Article  CAS  PubMed  Google Scholar 

  36. Andersson, U. et al. High mobility group 1 protein (HMG1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Orlova, V. V. et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J. 26, 1129–1139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rouhiainen, A., Tumova, S., Valmu, L., Kalkkinen, N. & Rauvala, H. Analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J. Leukocyte Biol. 81, 49–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Fairs, J. S. & McCarthy, D. J. J. Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals. Lancet 280, 682–685 (1962).

    Article  Google Scholar 

  40. Liu, F. T. & Rabinovich, G. A. Galectins as modulators of tumour progression. Nature Rev. Cancer 5, 29–41 (2005).

    Article  CAS  Google Scholar 

  41. Nakamura, H. et al. Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. Immunol. Lett. 42, 75–80 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Sano, H. et al. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J. Immunol. 165, 2156–2164 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Almkvist, J. & Karlsson, A. Galectins as inflammatory mediators. Glycoconj. J. 19, 575–581 (2004).

    Article  Google Scholar 

  44. Dai, S. Y. et al. Galectin-9 induces maturation of human monocyte-derived dendritic cells. J. Immunol. 175, 2974–2981 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Bertini, R. et al. Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells. J. Exp. Med. 189, 1783–1789 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schenk, H., Vogt, M., Droge, W. & Schulze-Osthoff, K. Thioredoxin as a potent costimulus of cytokine expression. J. Immunol. 156, 765–771 (1996).

    CAS  PubMed  Google Scholar 

  47. Panjwani, N. N., Popova, L. & Srivastava, P. K. Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J. Immunol. 168, 2997–3003 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Asea, A. et al. HSP70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nature Med. 6, 435–442 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Chen, W., Syldath, U., Bellmann, K., Burkart, V. & Kolb, H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J. Immunol. 162, 3212–3219 (1999).

    CAS  PubMed  Google Scholar 

  50. Wallin, R. P. et al. Heat-shock proteins as activators of the innate immune system. Trends Immunol. 23, 130–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. 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 

  52. Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Hefeneider, S. H. et al. Nucleosomes and DNA bind to specific cell-surface molecules on murine cells and induce cytokine production. Clin. Immunol. Immunopathol. 63, 245–251 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Decker, P., Singh-Jasuja, H., Haager, S., Kötter, I. & Rammensee, H. G. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J. Immunol. 174, 3326–3334 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Cronstein, B. N., Daguma, L., Nichols, D., Hutchison, A. J. & Williams, M. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. J. Clin. Invest. 85, 1150–1157 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Poelstra, K., Heynen, E. R., Baller, J. F., Hardonk, M. J. & Bakker, W. W. Modulation of anti-Thy1 nephritis in the rat by adenine nucleotides. Evidence for an anti-inflammatory role for nucleotidases. Lab. Invest. 66, 555–563 (1992).

    CAS  PubMed  Google Scholar 

  57. Zanetti, M. Cathelicidins, multifunctional peptides of the innate immunity. J. Leukocyte Biol. 75, 39–48 (2004).

    Article  PubMed  CAS  Google Scholar 

  58. Yang, D. et al. LL-37, the neutrophil-granule- and epithelial-cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med. 192, 1069–1074 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang, D. et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Carp, H. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J. Exp. Med. 155, 264–275 (1982).

    Article  CAS  PubMed  Google Scholar 

  61. Zhang, M. et al. Identification of the target self-antigens in reperfusion injury. J. Exp. Med. 203, 141–152 (2006). This paper shows that natural IgM antibodies bind myosin released from necrotic cells in ischaemia–reperfusion injury and stimulate inflammation by activating complement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Williams, J. P. et al. Intestinal reperfusion injury is mediated by IgM and complement. J. Appl. Physiol. 86, 938–942 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Weiser, M. R. et al. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J. Exp. Med. 183, 2343–2348 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Zhang, M. et al. The role of natural IgM in myocardial ischemia–reperfusion injury. J. Mol. Cell. Cardiol. 41, 62–67 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Zhang, M. et al. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury. Proc. Natl Acad. Sci. USA 101, 3886–3891 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hill, J. H. & Ward, P. A. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J. Exp. Med. 133, 885–900 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pinckard, R. N. et al. Antibody-independent activation of human C1 after interaction with heart subcellular membranes. J. Immunol. 110, 1376–1382 (1973).

    CAS  PubMed  Google Scholar 

  68. Pfister, R. R., Haddox, J. L. & Sommers, C. I. Injection of chemoattractants into normal cornea: a model of inflammation after alkali injury. Invest. Ophthalmol. Vis. Sci. 39, 1744–1750 (1998).

    CAS  PubMed  Google Scholar 

  69. Weathington, N. M. et al. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nature Med. 12, 317–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Smiley, S. T., King, J. A. & Hancock, W. W. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167, 2887–2894 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Taylor, K. R. et al. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J. Biol. Chem. 279, 17079–17084 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Wrenshall, L. E., Cerra, F. B., Carlson, A., Bach, F. H. & Platt, J. L. Regulation of murine splenocyte responses by heparan sulfate. J. Immunol. 147, 455–459 (1991).

    CAS  PubMed  Google Scholar 

  73. Kaplan, A. P. et al. The intrinsic coagulation/kinin-forming cascade: assembly in plasma and cell surfaces in inflammation. Adv. Immunol. 66, 225–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Tsan, M. F. & Gao, B. Endogenous ligands of Toll-like receptors. J. Leukocyte Biol. 76, 514–519 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukocyte Biol. 81, 1–5 (2006).

    Article  PubMed  CAS  Google Scholar 

  76. Park, J. S. et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370–7377 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. 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 

  78. Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Vabulas, R. M. et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J. Biol. Chem. 277, 20847–20853 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Biragyn, A. et al. Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science 298, 1025–1029 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Chen, C. J. et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin. Invest. 116, 2262–2271 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Warger, T. et al. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J. Biol. Chem. 281, 22545–22553 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Kokkola, R. et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand. J. Immunol. 61, 1–9 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Dumitriu, I. E. et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J. Immunol. 174, 7506–7515 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Delneste, Y. et al. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 17, 353–362 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Fan, S. T. & Edgington, T. S. Integrin regulation of leukocyte inflammatory functions. CD11b/CD18 enhancement of the tumor necrosis factor-α responses of monocytes. J. Immunol. 150, 2972–2980 (1993).

    CAS  PubMed  Google Scholar 

  91. Kobayashi, H. & Terao, T. Hyaluronic acid-specific regulation of cytokines by human uterine fibroblasts. Am. J. Physiol. 273, C1151–C1159 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Gregersen, P. K. & Behrens, T. W. Genetics of autoimmune diseases — disorders of immune homeostasis. Nature Rev. Genet. 7, 917–928 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Romson, J. L. et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67, 1016–1023 (1983).

    Article  CAS  PubMed  Google Scholar 

  94. Hall, T. S. et al. The role of leukocyte depletion in reducing injury to the lung after hypothermic ischemia. Curr. Surg. 44, 137–139 (1987).

    CAS  PubMed  Google Scholar 

  95. Sadasivan, K. K., Carden, D. L., Moore, M. B. & Korthuis, R. J. Neutrophil mediated microvascular injury in acute, experimental compartment syndrome. Clin. Orthop. Relat. Res. 339, 206–215 (1997).

    Article  Google Scholar 

  96. Liu, Z. X., Han, D., Gunawan, B. & Kaplowitz, N. Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 43, 1220–1230 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Ghio, A. J., Kennedy, T. P., Hatch, G. E. & Tepper, J. S. Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation. J. Appl. Physiol. 71, 657–665 (1991).

    Article  CAS  PubMed  Google Scholar 

  98. Dovi, J. V., He, L. K. & DiPietro, L. A. Accelerated wound closure in neutrophil-depleted mice. J. Leukocyte Biol. 73, 448–455 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Faouzi, S. et al. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-κB-independent, caspase-3-dependent pathway. J. Biol. Chem. 276, 49077–49082 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Huynh, M. L., Fadok, V. A. & Henson, P. M. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation. J. Clin. Invest. 109, 41–50 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ronnefarth, V. M. et al. TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus. J. Immunol. 177, 7740–7749 (2006).

    Article  PubMed  Google Scholar 

  102. Boule, M. W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin–immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tsan, M. F. & Gao, B. Cytokine function of heat shock proteins. Am. J. Physiol. Cell. Physiol. 286, C739–C744 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Schmitt, E., Gehrmann, M., Brunet, M., Multhoff, G. & Garrido, C. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J. Leukocyte Biol. 81, 15–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Melcher, A. et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nature Med. 4, 581–587 (1998). This paper shows that the expression of heat-shock proteins in tumour cells is increased by necrotic but not apoptotic cell death and is related to immunogenicity in vivo.

    Article  CAS  PubMed  Google Scholar 

  106. 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 

  107. Fredholm, B. B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 14, 1315–1323 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Idzko, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med. 13, 913–919 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. la Sala, A. et al. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate TH1 responses. J. Immunol. 166, 1611–1617 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Yang, D., Biragyn, A., Hoover, D. M., Lubkowski, J. & Oppenheim, J. J. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu. Rev. Immunol. 22, 181–215 (2004).

    Article  PubMed  CAS  Google Scholar 

  111. Davidson, D. J. et al. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J. Immunol. 172, 1146–1156 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Lillard, J. W. Jr, Boyaka, P. N., Chertov, O., Oppenheim, J. J. & McGhee, J. R. Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc. Natl Acad. Sci. USA 96, 651–656 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gawlowski, D. M., Benoit, J. N. & Granger, H. J. Microvascular pressure and albumin extravasation after leukocyte activation in hamster cheek pouch. Am. J. Physiol. 264, H541–H546 (1993).

    CAS  PubMed  Google Scholar 

  115. Sozzani, S. et al. Migration of dendritic cells in response to formyl peptides, C5a, and a distinct set of chemokines. J. Immunol. 155, 3292–3295 (1995).

    CAS  PubMed  Google Scholar 

  116. Mummert, D. I., Takashima, A., Ellinger, L. & Mummert, M. E. Involvement of hyaluronan in epidermal Langerhans cell maturation and migration in vivo. J. Dermatol. Sci. 33, 91–97 (2003). This paper shows that the interaction of hyaluronic acid with Langerhans cells contributes to the development of contact hypersensitivity in vivo by using a specific inhibitory peptide.

    Article  CAS  PubMed  Google Scholar 

  117. 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 

  118. Termeer, C. C. et al. Oligosaccharides of hyaluronan are potent activators of dendritic cells. J. Immunol. 165, 1863–1870 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Tobiasova-Czetoova, Z. et al. Effects of human plasma proteins on maturation of monocyte-derived dendritic cells. Immunol. Lett. 100, 113–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Mahnke, K., Bhardwaj, R. S., Luger, T. A., Schwarz, T. & Grabbe, S. Interaction of murine dendritic cells with collagen up-regulates allostimulatory capacity, surface expression of heat stable antigen, and release of cytokines. J. Leukocyte Biol. 60, 465–472 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Brand, U. et al. Influence of extracellular matrix proteins on the development of cultured human dendritic cells. Eur. J. Immunol. 28, 1673–1680 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Houghton, A. M. et al. Elastin fragments drive disease progression in a murine model of emphysema. J. Clin. Invest. 116, 753–759 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Adair-Kirk, T. L. et al. A site on laminin α5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis. J. Immunol. 171, 398–406 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to H.K. from the Kanae Foundation, Japan, and to K.L.R. from the National Institutes of Health, USA.

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Kenneth Rock's homepage

Glossary

Adjuvants

These are immunostimulatory agents that enhance adaptive immune responses to co-administered antigens during vaccination.

Primary and secondary necrotic cell death

Primary necrosis (oncosis) is a form of cell death that is characterized by vacuolization of the cytoplasm and swelling of the mitochondria, nucleus and cytoplasm that leads to rupture of the plasma membrane. Secondary necrosis is a process that occurs in apoptotic cells that are not cleared by phagocytes, in which the integrity of the plasma membrane is lost and the constituents of the cell are released.

Non-obese diabetic (NOD) mice

NOD mice spontaneously develop type 1 diabetes mellitus as a result of autoreactive T-cell-mediated destruction of pancreatic β-islet cells.

Galectins

These are lectins that bind a wide variety of glycoproteins and glycolipids containing β-galactoside. They have extracellular and intracellular functions, including the regulation of apoptosis, RAS signalling, cell adhesion and angiogenesis.

Natural IgM antibodies

Natural antibodies are present in individuals without immunization (although they might be stimulated by the host flora). They are mainly of the IgM isotype, have not undergone somatic mutations, and have low affinity but high crossreactivity for many microbial pathogens and self antigens.

Defensins

Defensins and cathelicidins are members of a family of small antimicrobial polypeptides that are abundant in neutrophils and epithelial cells. They contribute to host defence by disrupting the cytoplasmic membrane of microorganisms.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kono, H., Rock, K. How dying cells alert the immune system to danger. Nat Rev Immunol 8, 279–289 (2008). https://doi.org/10.1038/nri2215

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2215

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