Immunological Danger Signals


The conventional role of the immune system has been viewed as the first line of defence discriminating self from nonself. However, in the past decade, the innate immune response has proven to be more advanced sensing signals of danger, such as pathogen‐specific molecules (PAMPs, pathogen‐associated molecular patterns) or endogenous host‐derived signals released during cellular damage, while remaining unresponsive to normal host molecules, dietary antigens or commensal bacteria. The host response to invading microbial pathogens relies on both the innate and adaptive immune response. The danger theory of Matzinger (1994) proposed a similar model for the adaptive immune response in discriminating self from nonself. This theory proposed that the immune system does not react to foreign substances but instead responds to situations that are potentially harmful. These danger signals, or damage‐associated molecular patterns (DAMPs), released by damaged cells, can provide for a second signal which is necessary to activate the immune response while avoiding collateral damage in situations in which harmless nonself is present.

Key Concepts

  • According to the danger theory of Matzinger, the immune system does not merely distinguish whether an entity is foreign or not, it mainly determines whether it will cause damage to the body.
  • Damage‐associated molecular patterns (DAMP) are danger signals released during inflammatory stress such as burns, trauma and infection.
  • Each pathogen is recognised by its specific molecular signature or pathogen‐associated molecular pattern (PAMP).
  • Activation of the innate immune system relies on both pathogen‐specific molecules and endogenous danger signals.
  • DAMPs can be recognised by pattern‐recognition receptors on antigen‐presenting cells or by distinct receptors such as the receptor for advanced glycation end products (RAGE).
  • Key DAMPs that are recognised by Toll‐like receptors (TLRs) include heat shock proteins (HSPs), high‐mobility group box 1 (HMGB)‐1 and the S100 proteins.

Keywords: DAMPs; danger signals; innate immunity; pattern‐recognition receptors; PAMPs; inflammasome; HMGB‐1; heat shock proteins

Figure 1. Recognition of both PAMPs and DAMPs by PRRs activates the proinflammatory immune response during sterile and nonsterile inflammations. During infection, pathogen‐associated molecular patterns (PAMPs) are recognised by pattern‐recognition receptors (PRRs) on host cells, such as Toll‐like (TLRs) and NOD‐like receptors (NLRs). These receptors in turn activate the proinflammatory immune response releasing chemo‐ and cytokines, initiate cell death, recruit leucocytes and activate the coagulation and complement cascade. However, when cells become necrotic they can also release endogenous molecules called damage‐associated molecular patterns (DAMPs), which can be recognised either by PRRs or DAMP‐specific receptors (e.g. RAGE). Furthermore, on going infection can lead to tissue destruction, which propagates further release of DAMPs creating a vicious circle. On the other hand, sterile inflammation (trauma or burn) can also cause tissue destruction with the release of excessive amounts of DAMPs via necrotic cells causing inflammation in a similar manner as is seen during microbial invasion.


Achouiti A, Vogl T, Urban CF, et al. (2012) Myeloid‐related protein‐14 contributes to protective immunity in gram‐negative pneumonia derived sepsis. PLoS Pathogens 8: e1002987.

Akira S, Uematsu S and Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783–801.

Babelova A, Moreth K, Tsalastra‐Greul W, et al. (2009) Biglycan, a danger signal that activates the NLRP3 inflammasome via toll‐like and P2X receptors. Journal of Biological Chemistry 284: 24035–24048.

Bopp C, Bierhaus A, Hofer S, et al. (2008) Bench‐to‐bedside review: the inflammation‐perpetuating pattern‐recognition receptor RAGE as a therapeutic target in sepsis. Critical Care 12: 201.

Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN and Dagnelie PC (2006) Adenosine 5′‐triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacology and Therapeutics 112: 358–404.

Brinkmann V, Reichard U, Goosmann C, et al. (2004) Neutrophil extracellular traps kill bacteria. Science 303: 1532–1535.

Broz P and Monack DM (2011) Molecular mechanisms of inflammasome activation during microbial infections. Immunology Reviews 243: 174–190.

Chan JK, Roth J, Oppenheim JJ, et al. (2012) Alarmins: awaiting a clinical response. Journal of Clinical Investigation 122: 2711–2719.

Chen GY and Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nature Reviews Immunology 10: 826–837.

Corbin BD, Seeley EH, Raab A, et al. (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319: 962–965.

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

Fink SL and Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infection and Immunity 73: 1907–1916.

Foell D, Wittkowski H, Vogl T and Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage‐associated molecular pattern molecules. Journal of Leukocyte Biology 81: 28–37.

Gallucci S and Matzinger P (2001) Danger signals: SOS to the immune system. Current Opinion in Immunology 13: 114–119.

Hoebe K, Georgel P, Rutschmann S, et al. (2005) CD36 is a sensor of diacylglycerides. Nature 433: 523–527.

Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symposia on Quantitative Biology 54 (Pt 1): 1–13.

Janeway CA Jr (1992) The immune system evolved to discriminate infectious nonself from noninfectious self. Immunology Today 13: 11–16.

Jiang D, Liang J and Noble PW (2007) Hyaluronan in tissue injury and repair. Annual Review of Cell and Developmental Biology 23: 435–461.

de Jong HK, van der Poll T and Wiersinga WJ (2010) The systemic pro‐inflammatory response in sepsis. Journal of Innate Immunity 2: 422–430.

Kaplan MJ and Radic M (2012) Neutrophil extracellular traps: double‐edged swords of innate immunity. Journal of Immunology 189: 2689–2695.

Kawai T and Akira S (2010) The role of pattern‐recognition receptors in innate immunity: update on Toll‐like receptors. Nature Immunology 11: 373–384.

Kono H, Chen CJ, Ontiveros F and Rock KL (2010) Uric acid promotes an acute inflammatory response to sterile cell death in mice. Journal of Clinical Investigation 120: 1939–1949.

Lee CC, Avalos AM and Ploegh HL (2012) Accessory molecules for Toll‐like receptors and their function. Nature Reviews Immunology 12: 168–179.

Liu‐Bryan R, Scott P, Sydlaske A, Rose DM and Terkeltaub R (2005) 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 and Rheumatism 52: 2936–2946.

Martinon F, Mayor A and Tschopp J (2009) The inflammasomes: guardians of the body. Annual Review of Immunology 27: 229–265.

Masters SL, Dunne A, Subramanian SL, et al. (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL‐1beta in type 2 diabetes. Nature Immunology 11: 897–904.

Matz JM, Blake MJ, Tatelman HM, Lavoi KP and Holbrook NJ (1995) Characterization and regulation of cold‐induced heat shock protein expression in mouse brown adipose tissue. American Journal of Physiology 269: R38–R47.

Matzinger P (1994) Tolerance, danger, and the extended family. Annual Review of Immunology 12: 991–1045.

Matzinger P (1998) An innate sense of danger. Seminars in Immunology 10: 399–415.

Medzhitov R and Janeway C Jr (2000) Innate immunity. New England Journal of Medicine 343: 338–344.

Mellman I and Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106: 255–258.

Park JS, Svetkauskaite D, He Q, et al. (2004) Involvement of toll‐like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. Journal of Biological Chemistry 279: 7370–7377.

Pisetsky DS (2012) The origin and properties of extracellular DNA: from PAMP to DAMP. Clinical Immunology 144: 32–40.

van der Poll T and Opal SM (2008) Host‐pathogen interactions in sepsis. Lancet Infectious Diseases 8: 32–43.

Quintana FJ and Cohen IR (2005) Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. Journal of Immunology 175: 2777–2782.

Quintin J, Cheng SC, van der Meer JW and Netea MG (2014) Innate immune memory: towards a better understanding of host defense mechanisms. Current Opinion in Immunology 29: 1–7.

Ryckman C, McColl SR, Vandal K, et al. (2003a) Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air‐pouch model of acute gouty arthritis. Arthritis and Rheumatism 48: 2310–2320.

Ryckman C, Vandal K, Rouleau P, Talbot M and Tessier PA (2003b) Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. Journal of Immunology 170: 3233–3242.

Scaffidi P, Misteli T and Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418: 191–195.

Schlesinger MJ (1990) Heat shock proteins. Journal of Biological Chemistry 265: 12111–12114.

Schroder K and Tschopp J (2010) The inflammasomes. Cell 140: 821–832.

Seong SY and Matzinger P (2004) Hydrophobicity: an ancient damage‐associated molecular pattern that initiates innate immune responses. Nature Reviews Immunology 4: 469–478.

Stewart CR, Stuart LM, Wilkinson K, et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll‐like receptor 4 and 6 heterodimer. Nature Immunology 11: 155–161.

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

Taylor KR, Yamasaki K, Radek KA, et al. (2007) Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll‐like receptor 4, CD44, and MD‐2. Journal of Biological Chemistry 282: 18265–18275.

Tian J, Avalos AM, Mao SY, et al. (2007) Toll‐like receptor 9‐dependent activation by DNA‐containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunology 8: 487–496.

Urban CF, Ermert D, Schmid M, et al. (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathogens 5: e1000639.

Vabulas RM, Ahmad‐Nejad P, da Costa C, et al. (2001) Endocytosed HSP60s use toll‐like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin‐1 receptor signaling pathway in innate immune cells. Journal of Biological Chemistry 276: 31332–31339.

Vance RE (2000) Cutting edge: cutting edge commentary: a Copernican revolution? Doubts about the danger theory. Journal of Immunology 165: 1725–1728.

Vandal K, Rouleau P, Boivin A, et al. (2003) Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide. Journal of Immunology 171: 2602–2609.

Vogl T, Tenbrock K, Ludwig S, et al. (2007) Mrp8 and Mrp14 are endogenous activators of Toll‐like receptor 4, promoting lethal, endotoxin‐induced shock. Nature Medicine 13: 1042–1049.

Wang H, Bloom O, Zhang M, et al. (1999) HMG‐1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251.

Wiersinga WJ, Leopold SJ, Cranendonk DR and van der Poll T (2014) Host innate immune responses to sepsis. Virulence 5: 36–44.

Wittkowski H, Sturrock A, van Zoelen MA, et al. (2007) Neutrophil‐derived S100A12 in acute lung injury and respiratory distress syndrome. Critical Care Medicine 35: 1369–1375.

Wu C (1995) Heat shock transcription factors: structure and regulation. Annual Review of Cell and Developmental Biology 11: 441–469.

Yu M, Wang H, Ding A, et al. (2006) HMGB1 signals through toll‐like receptor (TLR) 4 and TLR2. Shock 26: 174–179.

van Zoelen MA, Vogl T, Foell D, et al. (2009a) Expression and role of myeloid‐related protein‐14 in clinical and experimental sepsis. American Journal of Respiratory and Critical Care Medicine 180: 1098–1106.

van Zoelen MA, Yang H, Florquin S, et al. (2009b) Role of toll‐like receptors 2 and 4, and the receptor for advanced glycation end products in high‐mobility group box 1‐induced inflammation in vivo. Shock 31: 280–284.

van Zoelen MA, Achouiti A and van der Poll T (2011) The role of receptor for advanced glycation endproducts (RAGE) in infection. Critical Care 15: 208.

Further Reading

Castellheim A, Brekke OL, Espevik T, Harboe M and Mollnes TE (2009) Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scandinavian Journal of Immunology 69: 479–491.

Jenne CN and Kubes P (2013) Immune surveillance by the liver. Nature Immunology 14: 996–1006.

Matzinger P (2007) Friendly and dangerous signals: is the tissue in control? Nature Immunology 8: 11–13.

Matzinger P and Kamala T (2011) Tissue‐based class control: the other side of tolerance. Nature Reviews Immunology 11: 221–230.

Pedra JH, Cassel SL and Sutterwala FS (2009) Sensing pathogens and danger signals by the inflammasome. Current Opinion in Immunology 21: 10–16.

Yu L, Wang L and Chen S (2010) Endogenous toll‐like receptor ligands and their biological significance. Journal of Cellular and Molecular Medicine 14: 2592–2603.

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de Jong, Hanna K, and Wiersinga, W Joost(Jan 2016) Immunological Danger Signals. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001210.pub2]