Sensing Necrotic Cells

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 738)


Multicellular organisms have developed ways to recognize potentially life-threatening events (danger signals). Classically, danger signals have been defined as exogenous, pathogen-associated molecular patterns (PAMPs) such as bacterial cell wall components (e.g., lipopolysaccharide and peptideglycan) or viral DNA/RNA. PAMPs interact with dedicated receptors on immune cells, so-called pattern recognition receptors (PRRs) and activate immune systems. A well-known family of PRRs is the toll-like receptors (TLRs) in which each member recognizes a specific set of PAMPs. However, not only exogenous pathogens but also several endogenous molecules released from necrotic cells (damaged self) also activate immune systems. These endogenous adjuvants are called damage-associated molecular patterns (DAMPs). It has been reported that high-mobility group box 1 protein (HMGB1), uric acid, heat shock proteins (HSPs) and nucleotides act as endogenous adjuvants. DAMPs are recognized by specific receptors (danger receptors) expressed mainly on antigen-presenting cells such as dendritic cells and macrophages and induce cell maturation and the production of inflammatory cytokines by activating the NF-kB pathway. In this chapter, we will review danger signals released from necrotic cells and its recognition receptors.


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  1. 1.
    Nagata S. Apoptosis by death factor. Cell 1997; 88:355–365.PubMedCrossRefGoogle Scholar
  2. 2.
    Vaux DL, Korsmeyer SJ. Cell death in development. Cell 1999; 96:245–254.PubMedCrossRefGoogle Scholar
  3. 3.
    Henson PM, Bratton DL, Fadok VA. Apoptotic cell removal. Curr Biol 2001; 11:R795–R805.PubMedCrossRefGoogle Scholar
  4. 4.
    Hengartner MO. Apoptosis: corralling the corpses. Cell 2001; 104:325–328.PubMedCrossRefGoogle Scholar
  5. 5.
    Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000; 407:784–788.PubMedCrossRefGoogle Scholar
  6. 6.
    Fadok VA, Bratton DL, Konowal A et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2 and PAF. J Clin Invest 1998; 101:890–898.PubMedCrossRefGoogle Scholar
  7. 7.
    Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002; 109:41–50.PubMedGoogle Scholar
  8. 8.
    Golstein P, Kroemer G. Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 2007; 32:37–43.PubMedCrossRefGoogle Scholar
  9. 9.
    do Vale A, Costa-Ramos C, Silva A et al. Systemic macrophage and neutrophil destruction by secondary necrosis induced by a bacterial exotoxin in a Gram-negative septicaemia. Cell Microbiol 2007; 9:988–1003.PubMedCrossRefGoogle Scholar
  10. 10.
    Brennan MA, Cookson BT. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 2000; 38:31–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Lenardo MJ, Angleman SB, Bounkeua V et al. Cytopathic killing of peripheral blood CD4(+) T-lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require env. J Virol 2002; 76:5082–5093.PubMedCrossRefGoogle Scholar
  12. 12.
    Borthwick NJ, Wickremasinghe RG, Lewin J et al. Activation-associated necrosis in human immunodeficiency virus infection. J Infect Dis 1999; 179:352–360.PubMedCrossRefGoogle Scholar
  13. 13.
    Benchoua A, Guegan C, Couriaud C et al. Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 2001; 21:7127–7134.PubMedGoogle Scholar
  14. 14.
    Unal-Cevik I, Kilinc M, Can A et al. Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke 2004; 35:2189–2194.PubMedCrossRefGoogle Scholar
  15. 15.
    Bobryshev YV, Babaev VR, Lord RS et al. Cell death in atheromatous plaque of the carotid artery occurs through necrosis rather than apoptosis. In Vivo 1997; 11:441–452.PubMedGoogle Scholar
  16. 16.
    James TN. The variable morphological coexistence of apoptosis and necrosis in human myocardial infarction: significance for understanding its pathogenesis, clinical course, diagnosis and prognosis. Coron Artery Dis 1998; 9:291–307.PubMedCrossRefGoogle Scholar
  17. 17.
    Silva MT, do Vale A, dos Santos NM. Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis 2008; 13:463–482.PubMedCrossRefGoogle Scholar
  18. 18.
    Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81:1–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Thomas JO, Travers AA. HMG1 and 2 and related ‘architectural’ DNA-binding proteins. Trends Biochem Sci 2001; 26:167–174.PubMedCrossRefGoogle Scholar
  20. 20.
    Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418:191–195.PubMedCrossRefGoogle Scholar
  21. 21.
    Park JS, Svetkauskaite D, He Q et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279:7370–7377.PubMedCrossRefGoogle Scholar
  22. 22.
    Muller S, Scaffidi P, Degryse B et al. New EMBO members’ review: the double life of HMGB1 chromatin protein: architectural factor and extracellular signal. EMBO J 2001; 20:4337–4340.PubMedCrossRefGoogle Scholar
  23. 23.
    Andersson U, Wang H, Palmblad K et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192:565–570.PubMedCrossRefGoogle Scholar
  24. 24.
    Messmer D, Yang H, Telusma G et al. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol 2004; 173:307–313.PubMedGoogle Scholar
  25. 25.
    Wang H, Bloom O, Zhang M et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285:248–251.PubMedCrossRefGoogle Scholar
  26. 26.
    Yang H, Ochani M, Li J et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004; 101:296–301.PubMedCrossRefGoogle Scholar
  27. 27.
    Rouhiainen A, Tumova S, Valmu L et al. Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J Leukoc Biol 2007; 81:49–58.PubMedCrossRefGoogle Scholar
  28. 28.
    Tian J, Avalos AM, Mao SY et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 2007; 8:487–496.PubMedCrossRefGoogle Scholar
  29. 29.
    Bianchi ME. HMGB1 loves company. J Leukoc Biol 2009; 86:573–576.PubMedCrossRefGoogle Scholar
  30. 30.
    Yanai H, Ban T, Wang Z et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 2009; 462:99–103.PubMedCrossRefGoogle Scholar
  31. 31.
    Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003; 425:516–521.PubMedCrossRefGoogle Scholar
  32. 32.
    Shi Y, Galusha SA, Rock KL. 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 2006; 176:3905–3908.PubMedGoogle Scholar
  33. 33.
    Martinon F, Petrilli V, Mayor A et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440:237–241.PubMedCrossRefGoogle Scholar
  34. 34.
    Basu S, Binder RJ, Suto R et al. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 2000; 12:1539–1546.PubMedCrossRefGoogle Scholar
  35. 35.
    Singh-Jasuja H, Toes RE, Spee P et al. Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 2000; 191:1965–1974.PubMedCrossRefGoogle Scholar
  36. 36.
    Asea A, Kraeft SK, Kurt-Jones EA et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6:435–442.PubMedCrossRefGoogle Scholar
  37. 37.
    Kol A, Lichtman AH, Finberg RW et al. Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 2000; 164:13–17.PubMedGoogle Scholar
  38. 38.
    Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nat Immunol 2000; 1:151–155.PubMedCrossRefGoogle Scholar
  39. 39.
    Basu S, Binder RJ, Ramalingam T et al. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 2001; 14:303–313.PubMedCrossRefGoogle Scholar
  40. 40.
    Wang Y, Kelly CG, Karttunen JT et al. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 2001; 15:971–983.PubMedCrossRefGoogle Scholar
  41. 41.
    Becker T, Hartl FU, Wieland F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 2002; 158:1277–1285.PubMedCrossRefGoogle Scholar
  42. 42.
    Millar DG, Garza KM, Odermatt B et al. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 2003; 9:1469–1476.PubMedCrossRefGoogle Scholar
  43. 43.
    Theriault JR, Mambula SS, Sawamura T et al. Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett 2005; 579:1951–1960.PubMedCrossRefGoogle Scholar
  44. 44.
    Delneste Y, Magistrelli G, Gauchat J et al. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 2002; 17:353–362.PubMedCrossRefGoogle Scholar
  45. 45.
    Theriault JR, Adachi H, Calderwood SK. Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 2006; 177:8604–8011.PubMedGoogle Scholar
  46. 46.
    Multhoff G. Activation of natural killer cells by heat shock protein 70. Int J Hyperthermia 2002; 18:576–585.PubMedCrossRefGoogle Scholar
  47. 47.
    Alexopoulou L, Holt AC, Medzhitov R et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413:732–738.PubMedCrossRefGoogle Scholar
  48. 48.
    Kariko K, Ni H, Capodici J et al. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 2004; 279:12542–12550.PubMedCrossRefGoogle Scholar
  49. 49.
    Ishii KJ, Suzuki K, Coban C et al. Genomic DNA released by dying cells induces the maturation of APCs. J Immunol 2001; 167:2602–2607.PubMedGoogle Scholar
  50. 50.
    Lazarowski ER, Homolya L, Boucher RC et al. Direct demonstration of mechanically induced release of cellular UTP and its implication for uridine nucleotide receptor activation. J Biol Chem 1997; 272:24348–24354.PubMedCrossRefGoogle Scholar
  51. 51.
    Iyer SS, Pulskens WP, Sadler JJ et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci USA 2009; 106:20388–20393.PubMedCrossRefGoogle Scholar
  52. 52.
    Marriott I, Inscho EW, Bost KL. Extracellular uridine nucleotides initiate cytokine production by murine dendritic cells. Cell Immunol 1999; 195:147–156.PubMedCrossRefGoogle Scholar
  53. 53.
    Schnurr M, Then F, Galambos P et al. Extracellular ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells. J Immunol 2000; 165:4704–4709.PubMedGoogle Scholar
  54. 54.
    Mutini C, Falzoni S, Ferrari D et al. Mouse dendritic cells express the P2X7 purinergic receptor: characterization and possible participation in antigen presentation. J Immunol 1999; 163:1958–1965.PubMedGoogle Scholar
  55. 55.
    Huysamen C, Willment JA, Dennehy KM et al. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J Biol Chem 2008; 283:16693–16701.PubMedCrossRefGoogle Scholar
  56. 56.
    Sancho D, Mourao-Sa D, Joffre OP et al. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest 2008; 118:2098–2110.PubMedCrossRefGoogle Scholar
  57. 57.
    Iyoda T, Shimoyama S, Liu K et al. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 2002; 195:1289–1302.PubMedCrossRefGoogle Scholar
  58. 58.
    Qiu CH, Miyake Y, Kaise H et al. Novel subset of CD8 alpha+ dendritic cells localized in the marginal zone is responsible for tolerance to cell-associated antigens. J Immunol 2009; 182:4127–4136.PubMedCrossRefGoogle Scholar
  59. 59.
    Robinson MJ, Sancho D, Slack EC et al. Myeloid C-type lectins in innate immunity. Nat Immunol 2006; 7:1258–1265.PubMedCrossRefGoogle Scholar
  60. 60.
    Cavassani KA, Ishii M, Wen H et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med 2008; 205:2609–2621.PubMedCrossRefGoogle Scholar
  61. 61.
    Flornes LM, Bryceson YT, Spurkland A et al. Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex. Immunogenetics 2004; 56:506–517.PubMedCrossRefGoogle Scholar
  62. 62.
    Matsumoto M, Tanaka T, Kaisho T et al. A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. J Immunol 1999; 163:5039–5048.PubMedGoogle Scholar
  63. 63.
    Yamasaki S, Ishikawa E, Sakuma M et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 2008; 9:1179–1188.PubMedCrossRefGoogle Scholar
  64. 64.
    Mimori T, Hinterberger M, Pettersson I et al. Autoantibodies to the U2 small nuclear ribonucleoprotein in a patient with scleroderma-polymyositis overlap syndrome. J Biol Chem 1984; 259:560–565.PubMedGoogle Scholar
  65. 65.
    Iyoda T, Nagata K, Akashi M et al. Neutrophils accelerate macrophage-mediated digestion of apoptotic cells in vivo as well as in vitro. J Immunol 2005; 175:3475–3483.PubMedGoogle Scholar
  66. 66.
    Yamasaki S, Matsumoto M, Takeuchi O et al. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc Natl Acad Sci USA 2009; 106:1897–1902.PubMedCrossRefGoogle Scholar
  67. 67.
    Ishikawa E, Ishikawa T, Morita YS et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 2009; 206:2879–2888.PubMedCrossRefGoogle Scholar
  68. 68.
    Azuma I, Seya T. Development of immunoadjuvants for immunotherapy of cancer. Int Immunopharmacol 2001; 1:1249–1259.PubMedCrossRefGoogle Scholar
  69. 69.
    Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989; 54 Pt 1:1–13.PubMedCrossRefGoogle Scholar
  70. 70.
    Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298–300.PubMedCrossRefGoogle Scholar
  71. 71.
    Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 2004; 4:469–478.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Division of Molecular Immunology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan

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