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Damage-associated molecular pattern

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]

History

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.[citation needed]

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]

Examples

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]

HMGB1

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).[15] 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.[citation needed]

DNA and RNA

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.[16]

S100 proteins

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.[17][18][19][20][21][15]

Purine metabolites

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.[22] ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death.[23] Extracellular ATP triggers mast cell degranulation by signaling through P2X7 receptors.[24][22][25] Similarly, adenosine triggers degranulation through P1 receptors. Uric acid is also an endogenous danger signal released by injured cells.[26]

Mono and polysaccharides

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

Clinical targets in various disorders

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].

References

  1. ^ a b Seong SY, Matzinger P (June 2004). "Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses". Nature Reviews. Immunology. 4 (6): 469–78. doi:10.1038/nri1372. PMID 15173835. 
  2. ^ Janeway C (September 1989). "Immunogenicity signals 1,2,3 ... and 0". Immunology Today. 10 (9): 283–6. doi:10.1016/0167-5699(89)90081-9. PMID 2590379. 
  3. ^ Rubartelli A, Lotze MT (October 2007). "Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox". Trends in Immunology. 28 (10): 429–36. doi:10.1016/j.it.2007.08.004. PMID 17845865. 
  4. ^ a b Farkas AM, Kilgore TM, Lotze MT (December 2007). "Detecting DNA: getting and begetting cancer". Current Opinion in Investigational Drugs. 8 (12): 981–6. PMID 18058568. 
  5. ^ Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, Arfors KE, Messmer K (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. doi:10.1097/00007890-199401001-00010. PMID 8310510. 
  6. ^ Matzinger P (1994). "Tolerance, danger, and the extended family". Annual Review of Immunology. 12: 991–1045. doi:10.1146/annurev.iy.12.040194.005015. PMID 8011301. 
  7. ^ Panayi GS, Corrigall VM, Henderson B (August 2004). "Stress cytokines: pivotal proteins in immune regulatory networks; Opinion". Current Opinion in Immunology. 16 (4): 531–4. doi:10.1016/j.coi.2004.05.017. PMID 15245751. 
  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. doi:10.1038/nature00858. PMID 12110890. 
  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". Journal of Immunology. 177 (2): 1272–81. doi:10.4049/jimmunol.177.2.1272. PMID 16818787. 
  10. ^ Boeynaems JM, Communi D (May 2006). "Modulation of inflammation by extracellular nucleotides". The Journal of Investigative Dermatology. 126 (5): 943–4. doi:10.1038/sj.jid.5700233. PMID 16619009. 
  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". Pharmacology & Therapeutics. 112 (2): 358–404. doi:10.1016/j.pharmthera.2005.04.013. PMID 16784779. 
  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. Bibcode:2003Natur.425..516S. doi:10.1038/nature01991. PMID 14520412. 
  13. ^ Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A (October 2002). "The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway". EMBO Reports. 3 (10): 995–1001. doi:10.1093/embo-reports/kvf198. PMC 1307617Freely accessible. PMID 12231511. 
  14. ^ Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (July 1999). "HMG-1 as a late mediator of endotoxin lethality in mice". Science. 285 (5425): 248–51. doi:10.1126/science.285.5425.248. PMID 10398600. 
  15. ^ a b Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (December 2013). "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology. 56 (4): 739–44. doi:10.1016/j.molimm.2013.07.008. PMID 23954397. 
  16. ^ Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, Martinez L, Greidinger EL, Yu BD, Gallo RL (August 2012). "Ultraviolet radiation damages self noncoding RNA and is detected by TLR3". Nature Medicine. 18 (8): 1286–90. doi:10.1038/nm.2861. PMC 3812946Freely accessible. PMID 22772463. 
  17. ^ Diederichs S, Bulk E, Steffen B, Ji P, Tickenbrock L, Lang K, Zänker KS, Metzger R, Schneider PM, Gerke V, Thomas M, Berdel WE, Serve H, Müller-Tidow C (August 2004). "S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer". Cancer Research. 64 (16): 5564–9. doi:10.1158/0008-5472.CAN-04-2004. PMID 15313892. 
  18. ^ Emberley ED, Murphy LC, Watson PH (2004). "S100A7 and the progression of breast cancer". Breast Cancer Research. 6 (4): 153–9. doi:10.1186/bcr816. PMC 468668Freely accessible. PMID 15217486. 
  19. ^ Emberley ED, Murphy LC, Watson PH (August 2004). "S100 proteins and their influence on pro-survival pathways in cancer". Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire. 82 (4): 508–15. doi:10.1139/o04-052. PMID 15284904. 
  20. ^ Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F, Weber DJ (August 2004). "Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells". The Journal of Biological Chemistry. 279 (32): 34071–7. doi:10.1074/jbc.M405419200. PMID 15178678. 
  21. ^ 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)". Biochemical and Biophysical Research Communications. 322 (4): 1111–22. doi:10.1016/j.bbrc.2004.07.096. PMID 15336958. 
  22. ^ a b Russo MV, McGavern DB (October 2015). "Immune Surveillance of the CNS following Infection and Injury". Trends in Immunology. 36 (10): 637–50. doi:10.1016/j.it.2015.08.002. PMC 4592776Freely accessible. PMID 26431941. 
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  24. ^ Kurashima Y, Kiyono H (March 2014). "New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development". Experimental & Molecular Medicine. 46 (3): e83. doi:10.1038/emm.2014.7. PMC 3972796Freely accessible. PMID 24626169. 
  25. ^ Kurashima Y, Amiya T, Nochi T, Fujisawa K, Haraguchi T, Iba H, Tsutsui H, Sato S, Nakajima S, Iijima H, Kubo M, Kunisawa J, Kiyono H (2012). "Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors". Nature Communications. 3: 1034. Bibcode:2012NatCo...3E1034K. doi:10.1038/ncomms2023. PMC 3658010Freely accessible. PMID 22948816. 
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Further reading