Damage-associated molecular pattern

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Damage-associated molecular patterns (DAMPs),[1] also known as danger-associated molecular patterns, danger signals, and alarmin, are host biomolecules that can initiate and perpetuate a noninfectious inflammatory response. In contrast, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response.[2] A subset of DAMPs are nuclear or cytosolic proteins. When released outside the cell or exposed on the surface of the cell following tissue injury, they move from a reducing to an oxidizing milieu, which results in their denaturation.[3] Also, following necrosis (a kind of cell death), tumor DNA is released outside the nucleus, and outside the cell, and becomes a DAMP.[4]


Two papers appearing in 1994 presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first[5] came from transplant surgeons who conducted a prospective randomized double-blind placebo-controlled trial. Administration of recombinant human superoxide dismutase (rh-SOD) in recipients of cadaveric renal allografts demonstrated prolonged patient and graft survival with improvement in both acute and chronic rejection events. They speculated that the effect was related to its antioxidant action on the initial ischemia/reperfusion injury of the renal allograft, thereby reducing the immunogenicity of the allograft and the "grateful dead" or stressed cells. Thus free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses.

The second [6] suggested the possibility that the immune system detected "danger", through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. Thus these two papers together presaged the modern sense of the role of DAMPs and redox reviewed here, important apparently for both plant and animal resistance to pathogens and the response to cellular injury or damage. Although many immunologists had earlier noted that various "danger signals" could initiate innate immune responses, the "DAMP" was first described by Seong and Matzinger in 2004.[1]


DAMPs vary greatly depending on the type of cell (epithelial or mesenchymal) and injured tissue. Protein DAMPs include intracellular proteins, such as heat-shock proteins[7] or HMGB1[8] (high-mobility group box 1), and proteins derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments.[9] Examples of non-protein DAMPs include ATP,[10][11] uric acid,[12] heparin sulfate and DNA.[4]


The chromatin-associated protein high-mobility group box 1 (HMGB1) is a prototypical leaderless secreted protein [LSP] secreted by hematopoietic cells through a lysosome-mediated pathway.[13] It is a major mediator of endotoxin shock[14] and acts on several immune cells to trigger inflammatory responses as a DAMP.[8] Known receptors for HMGB1 include TLR2, TLR4 and RAGE (receptor for advanced glycation endproducts). HMGB1 can induce dendritic cell maturation via upregulation of CD80, CD83, CD86 and CD11c, induce production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8) as well as upregulate expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells.

DNA and RNA[edit]

The presence of DNA anywhere other than the nucleus or mitochondria is perceived as a DAMP and triggers responses mediated by TLR9 and DAI that drive cellular activation and immunoreactivity. Interestingly, some tissues such as the gut are inhibited by DNA in their immune response (this needs a reference, and may be a misinterpretation of what the gut does). Similarly, damaged RNAs released from UVB-exposed keratinocytes activate TLR3 on intact keratinocytes. TLR3 activation stimulates TNF-alpha and IL-6 production, which initiate the cutaneous inflammation associated with sunburn.[15]

S100 proteins[edit]

S100 is a multigenic family of calcium modulated proteins involved in intracellular and extracellular regulatory activities with a connection to cancer as well as tissue, particularly neuronal, injury.[16][17][18][19][20]

Purine metabolites[edit]

Nucleotides (e.g., ATP) and nucleosides (e.g., adenosine) that have reached the extracellular space can also serve as danger signals by signaling through purinergic receptors.[21] ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death.[22] Extracellular ATP triggers mast cell degranulation by signaling through P2X7 receptors.[23][21][24] Similarly, adenosine triggers degranulation through P1 receptors. Uric acid is also an endogenous danger signal released by injured cells.[25]

Hyaluronan fragments[edit]

The ability of the immune system to recognize hyaluronan fragments is one example of how DAMPs can be glycans or glycoconjugates.[26]

Clinical targets in various disorders[edit]

Theoretically, the application of therapeutics in this area to treat disorders as arthritis, cancer, ischemia-reperfusion, myocardial infarction and stroke could include options as:

  1. Preventing DAMP release [proapoptotic therapies; platinums; ethyl pyruvate];
  2. Neutralizing or blocking DAMPs extracellularly [anti-HMGB1; rasburicase; sRAGE, etc.];
  3. Blocking the DAMP receptors or their signaling [RAGE small molecule antagonists; TLR4 antagonists; antibodies to DAMP-R].


  1. ^ a b Seong SY, Matzinger P (2004). "Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses". Nature Reviews Immunology. 4 (6): 469–478. PMID 15173835. doi:10.1038/nri1372. 
  2. ^ Janeway C (September 1989). "Immunogenicity signals 1,2,3 ... and 0". Immunol. Today. 10 (9): 283–6. PMID 2590379. doi:10.1016/0167-5699(89)90081-9. 
  3. ^ Rubartelli A, Lotze MT (October 2007). "Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox". Trends Immunol. 28 (10): 429–36. PMID 17845865. doi:10.1016/j.it.2007.08.004. 
  4. ^ a b Farkas AM, Kilgore TM, Lotze MT (December 2007). "Detecting DNA: getting and begetting cancer". Curr Opin Investig Drugs. 8 (12): 981–6. PMID 18058568. 
  5. ^ Land W, Schneeberger H, Schleibner S, et al. (January 1994). "The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants". Transplantation. 57 (2): 211–7. PMID 8310510. doi:10.1097/00007890-199401001-00010. 
  6. ^ Matzinger P (1994). "Tolerance, danger, and the extended family". Annu. Rev. Immunol. 12: 991–1045. PMID 8011301. doi:10.1146/annurev.iy.12.040194.005015. 
  7. ^ Panayi GS, Corrigall VM, Henderson B (August 2004). "Stress cytokines: pivotal proteins in immune regulatory networks; Opinion". Curr. Opin. Immunol. 16 (4): 531–4. PMID 15245751. doi:10.1016/j.coi.2004.05.017. 
  8. ^ a b Scaffidi P, Misteli T, Bianchi ME (July 2002). "Release of chromatin protein HMGB1 by necrotic cells triggers inflammation". Nature. 418 (6894): 191–5. PMID 12110890. doi:10.1038/nature00858. 
  9. ^ Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR (July 2006). "Hyaluronan fragments act as an endogenous danger signal by engaging TLR2". J. Immunol. 177 (2): 1272–81. PMID 16818787. doi:10.4049/jimmunol.177.2.1272. 
  10. ^ Boeynaems JM, Communi D (May 2006). "Modulation of inflammation by extracellular nucleotides". J. Invest. Dermatol. 126 (5): 943–4. PMID 16619009. doi:10.1038/sj.jid.5700233. 
  11. ^ Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC (November 2006). "Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation". Pharmacol. Ther. 112 (2): 358–404. PMID 16784779. doi:10.1016/j.pharmthera.2005.04.013. 
  12. ^ Shi Y, Evans JE, Rock KL (October 2003). "Molecular identification of a danger signal that alerts the immune system to dying cells". Nature. 425 (6957): 516–21. PMID 14520412. doi:10.1038/nature01991. 
  13. ^ Gardella S, Andrei C, Ferrera D, et al. (October 2002). "The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway". EMBO Rep. 3 (10): 995–1001. PMC 1307617Freely accessible. PMID 12231511. doi:10.1093/embo-reports/kvf198. 
  14. ^ Wang H, Bloom O, Zhang M, et al. (July 1999). "HMG-1 as a late mediator of endotoxin lethality in mice". Science. 285 (5425): 248–51. PMID 10398600. doi:10.1126/science.285.5425.248. 
  15. ^ Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, Martinez L, Greidinger EL, Yu BD, Gallo RL (2012). "Ultraviolet radiation damages self noncoding RNA and is detected by TLR3". Nature Medicine. 18: 1286–1290. PMC 3812946Freely accessible. PMID 22772463. doi:10.1038/nm.2861. 
  16. ^ Diederichs S, Bulk E, Steffen B, et al. (August 2004). "S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer". Cancer Res. 64 (16): 5564–9. PMID 15313892. doi:10.1158/0008-5472.CAN-04-2004. 
  17. ^ Emberley ED, Murphy LC, Watson PH (2004). "S100A7 and the progression of breast cancer". Breast Cancer Res. 6 (4): 153–9. PMC 468668Freely accessible. PMID 15217486. doi:10.1186/bcr816. 
  18. ^ Emberley ED, Murphy LC, Watson PH (August 2004). "S100 proteins and their influence on pro-survival pathways in cancer". Biochem. Cell Biol. 82 (4): 508–15. PMID 15284904. doi:10.1139/o04-052. 
  19. ^ Lin J, Yang Q, Yan Z, et al. (August 2004). "Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells". J. Biol. Chem. 279 (32): 34071–7. PMID 15178678. doi:10.1074/jbc.M405419200. 
  20. ^ Marenholz I, Heizmann CW, Fritz G (October 2004). "S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature)". Biochem. Biophys. Res. Commun. 322 (4): 1111–22. PMID 15336958. doi:10.1016/j.bbrc.2004.07.096. 
  21. ^ a b Russo MV, McGavern DB (2015). "Immune Surveillance of the CNS following Infection and Injury". Trends Immunol. 36 (10): 637–50. PMC 4592776Freely accessible. PMID 26431941. doi:10.1016/j.it.2015.08.002. 
  22. ^ Zeh HJ, Lotze MT (2005). "Addicted to death: invasive cancer and the immune response to unscheduled cell death". J. Immunother. 28 (1): 1–9. PMID 15614039. doi:10.1097/00002371-200501000-00001. 
  23. ^ Kurashima Y, Kiyono H (2014). "New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development". Exp. Mol. Med. 46: e83. PMC 3972796Freely accessible. PMID 24626169. doi:10.1038/emm.2014.7. In the inflamed tissues, MCs are degranulated, and therefore it is important to elucidate the molecular mechanisms of MC activation. Ig-free light chains (IgLCs), which had been considered as by-products of immunoglobulin production by B cells, are involved in various inflammatory disorders.41 Increased serum concentrations of Ig-free light chains and their presence in colon specimens from IBD patients have been reported.41 Ig-free light chains bind to MCs (Figure 2) and increase vascular permeability in the colon in a mouse model of IBD.41 Yet, MC activation is also observed in B cell-deficient mice; therefore, we have suggested the existence of multiple MC activators during intestinal inflammation.40 ...

    Extracellular adenosine triphosphate (ATP) is considered as one of the danger-associated molecular patterns.42, 43 ATP is released from necrotic cells, commensal bacteria and activated monocytes.42, 43 MCs may also release or regenerate ATP to the extracellular compartments.40 ATP levels are increased in the peritoneal cavity of mice with graft-versus-host disease.44 ATP release has been reported to be significantly higher in colorectal biopsies from mice with colitis than in those from control mice.40 Extracellular ATP concentration is tightly regulated in vivo to maintain immune homeostasis.42, 43 In mice lacking the ectonucleotidase CD39, which dephosphorylates extracellular ATP, intestinal inflammation in experimental colitis is exacerbated.45 These observations indicate the importance of extracellular ATP in intestinal inflammation. Extracellular ATP induces a wide range of pathophysiological responses via activation of purinergic P2 receptors at the cell surface.42, 43 P2X purinoceptors (P2X1–7) act as ATP-gated ion channels.42 P2X7 is involved in various inflammatory conditions, such as asthma, contact hypersensitivity and graft-versus-host diseases.44, 46, 47 In the colon tissue, MCs express high levels of P2X7.40 Our and other previous studies indicate that extracellular ATP stimulates MCs to release inflammatory cytokines (for example, IL-1β, IL-6 and TNFα), chemokines (for example, CCL2 and CXCL2) and lipid mediators (for example, leukotriene B4) in a P2X7-dependent manner (Figure 2);40, 48 these compounds play a critical role in the MC-mediated intestinal mucosal inflammation. Furthermore, P2X7-expressing MCs accumulate at the inflammatory sites in the colons of Crohn's disease patients.40
  24. ^ Kurashima Y, Amiya T, Nochi T, et al. (2012). "Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors". Nat Commun. 3: 1034. PMC 3658010Freely accessible. PMID 22948816. doi:10.1038/ncomms2023. Here, we showed that colitis aggravated by P2X7-mediated activation of MCs was independent of the inflammasome pathway, and that P2X7-mediated activation of MCs promoted TNFα production by effector cells to further promote intestinal inflammation44. Our findings also suggest that MCs exacerbate inflammation by recruiting neutrophils to produce abundant TNFα, but less IL-10 than is produced by other cells (for example, eosinophils, DCs and macrophages; Supplementary Fig. S10d). This neutrophil recruitment was mediated by the production of IL-1β, LTs and chemokines, which are potential targets for the treatment of colitis. Mice with experimentally induced colitis that lack CXCR2 or 5-LO (a key enzyme for converting arachidonic acid to LTs), as well as mice treated with inhibitors of CCR2, CXCR2 or 5-LO, show reduced inflammation and less neutrophil recruitment in their colons33,45,46. Moreover, given that ATP promotes neutrophil migration47, it is possible that P2X7-dependent LT and chemokine production, as well as ATP generation via AK2 and ATP synthase from MCs, could amplify neutrophil infiltration of the colon. These data collectively indicate that MCs are key factors in the induction of intestinal inflammation and also recruit neutrophils to heighten inflammatory responses. P2X7-dependent MC activation could, therefore, be a target for the treatment of intestinal inflammation. 
  25. ^ Shi Y.; Evans J. E.; et al. (2003). "Molecular identification of a danger signal that alerts the immune system to dying cells". Nature. 425 (6957): 516–21. PMID 14520412. doi:10.1038/nature01991. 
  26. ^ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. PMC 4340844Freely accessible. PMID 25578468. doi:10.1016/j.jaut.2014.12.002. 

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