Biology:Damage-associated molecular pattern

From HandWiki
Short description: Type of molecules within cells

Damage-associated molecular patterns (DAMPs)[1] are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen.[2] They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen.[3] Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor.[4] Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process.[5] As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α.[3] In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response.[6] Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury.[7] This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function.[7] Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.[3]

Overview

DAMPs and their receptors are characterized as:[3]

Table 1. List of DAMPs, their origins, and their receptors
Origin Major DAMPs Receptors
Extracellular matrix Biglycan TLR2, TLR4, NLRP3
Decorin TLR2, TLR4
Versican TLR2, TLR6, CD14
LMW hyaluronan TLR2, TLR4, NLRP3
Heparan sulfate TLR4
Fibronectin (EDA domain) TLR4
Fibrinogen TLR4
Tenascin C TLR4
Intracellular compartments Cytosol Uric Acid NLRP3, P2X7
S100 proteins TLR2, TLR4, RAGE
Heat-shock proteins TLR2, TLR4, CD91
ATP P2X7, P2Y2
F-actin DNGR-1
Cyclophilin A CD147
Aβ TLR2, NLRP1, NLRP3, CD36, RAGE
Nuclear Histones TLR2, TLR4
HMGB1 TLR2, TLR4, RAGE
HMGN1 TLR4
IL-1α IL-1R
IL-33 ST2
SAP130 Mincle
DNA TLR9, AIM2
RNA TLR3, TLR7, TLR8, RIG-I, MDA5
Mitochondria mtDNA TLR9
TFAM RAGE
Formyl peptide FPR1
mROS NLRP3
Endoplasmic reticulum Calreticulin CD91
Granule Defensins TLR4
Cathelicidin (LL37) P2X7, FPR2
Eosinophil-derived neurotoxin TLR2
Granulysin TLR4
Plasma membrane Syndecans TLR4
Glypicans TLR4

History

Two papers appearing in 1994 anticipated the deeper understanding of innate immune reactivity, pointing towards the subsequent understanding of the nature of the adaptive immune response. The first[8] 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 SOD's antioxidant action on the initial ischemia/reperfusion injury of the renal allograft, thereby reducing the immunogenicity of the allograft. Thus, free radical-mediated reperfusion injury was seen to contribute to the process of innate and subsequent adaptive immune responses.[9]

The second study[10] suggested the possibility that the immune system detected "danger", through a series of what is now called damage-associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. Thus, these papers anticipated the modern sense of the role of DAMPs and redox, 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, but they all share the common feature of stimulating an innate immune response within an organism.[2]

  • Protein DAMPs include intracellular proteins, such as heat-shock proteins[11] or HMGB1,[12] and materials derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments.[13]
  • Non-protein DAMPs include ATP,[14][15] uric acid,[16] heparin sulfate and DNA.[17]

In humans

Protein DAMPs

  1. High-mobility group box 1: HMGB1, a member of the HMG protein family, is a prototypical chromatin-associated LSP (leaderless secreted protein), secreted by hematopoietic cells through a lysosome-mediated pathway.[18] HMGB1 is a major mediator of endotoxin shock[19] and is recognized as a DAMP by certain immune cells, triggering an inflammatory response.[12] It is known to induce inflammation by activating NF-kB pathway by binding to TLR, TLR4, TLR9, and RAGE (receptor for advanced glycation end products).[20] HMGB1 can also induce dendritic cell maturation via upregulation of CD80, CD83, CD86 and CD11c, and the production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8), and it can lead to increased expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells.[21]
  1. 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. Some tissues, such as the gut, are inhibited by DNA in their immune response because the gut is filled with trillions of microbiota, which help break down food and regulate the immune system.[22] Without being inhibited by DNA, the gut would detect these microbiota as invading pathogens, and initiate a inflammatory response, which would be detrimental for the organism's health because while the microbiota may be foreign molecules inside the host, they are crucial in promoting host health.[22] 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.[23]
  1. 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.[24][25][26][27][28][20] Their main function is the management of calcium storage and shuffling. Although they have various functions, including cell proliferation, differentiation, migration, and energy metabolism, they also act as DAMPs by interacting with their receptors (TLR2, TLR4, RAGE) after they are released from phagocytes.[3]
  1. Mono- and polysaccharides: The ability of the immune system to recognize hyaluronan fragments is one example of how DAMPs can be made of sugars.[29]

Nonprotein DAMPs

  • 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.[30] ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death.[31] Extracellular ATP triggers mast cell degranulation by signaling through P2X7 receptors.[32][30][33] Similarly, adenosine triggers degranulation through P1 receptors. Uric acid is also an endogenous danger signal released by injured cells.[29] Adenosine triphosphate (ATP) and uric acid, which are purine metabolites, activate NLR family, pyrin domain containing (NLRP) 3 inflammasomes to induce IL-1β and IL-18.[3]

In plants

DAMPs in plants have been found to stimulate a fast immune response, but without the inflammation that characterizes DAMPs in mammals.[34] Just as with mammalian DAMPs, plant DAMPs are cytosolic in nature and are released into the extracellular space following damage to the cell caused by either trauma or pathogen.[35] The major difference in the immune systems between plants and mammals is that plants lack an adaptive immune system, so plants can not determine which pathogens have attacked them before and thus easily mediate an effective immune response to them. To make up for this lack of defense, plants use the pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) pathways to combat trauma and pathogens. PTI is the first line of defense in plants and is triggered by PAMPs to initiate signaling throughout the plant that damage has occur to a cell. Along with the PTI, DAMPs are also released in response to this damage, but as mentioned earlier they do not initiate an inflammatory response like their mammalian counterparts. The main role of DAMPs in plants is to act as mobile signals to initiate wounding responses and to promote damage repair. A large overlap occurs between the PTI pathway and DAMPs in plants, and the plant DAMPs effectively operate as PTI amplifiers. The ETI always occurs after the PTI pathway and DAMP release, and is a last resort response to the pathogen or trauma that ultimately results in programmed cell death. The PTI- and ETI-signaling pathways are used in conjunction with DAMPs to rapidly signal the rest of the plant to activate its innate immune response and fight off the invading pathogen or mediate the healing process from damage caused by trauma.[36]

Plant DAMPs and their receptors are characterized as:[35]

Table 2. List of plant DAMPs, their structures, sources, receptors, and observed plant species
Category DAMP Molecular structure or epitope Source or precursor Receptor or signaling regulator Species
Epidermis cuticle Cutin monomers C16 and C18 hydroxy and epoxy fatty acids Epidermis cuticle Unknown Arabidopsis thaliana, Solanum lycopersicum
Cell wall polysaccharide fragments or degrading products OGs Polymers of 10–15 α-1-4-linked GalAs Cell wall pectin WAK1 (A. thaliana) A. thaliana, G. max, N. tabacum
Cellooligomers Polymers of 2–7 β-1,4-linked glucoses Cell wall cellulose Unknown A. thaliana
Xyloglucan oligosaccharides Polymers of β-1,4-linked glucose with xylose, galactose, and fructose side chains Cell-wall hemicellulose Unknown A. thaliana, Vitis vinifera
Methanol Methanol Cell wall pectin Unknown A. thaliana, Nicotiana tabacum
Apoplastic peptides and proteins CAPE1 11-aa peptide Apoplastic PR1 Unknown A. thaliana, S. lycopersicum
GmSUBPEP 12-aa peptide Apoplastic subtilase Unknown Glycine max
GRIp 11-aa peptide Cytosolic GRI PRK5 A. thaliana
Systemin 18-aa peptide (S. lycopersicum) Cytosolic prosystemin SYR1/2 (S. lycopersicum) Some Solanaceae species
HypSys 15-, 18-, or 20-aa peptides Apoplastic or cytoplasmic preproHypSys Unknown Some Solanaceae species
Peps 23~36-aa peptides (A. thaliana) Cytosolic and vacuolar PROPEPs PEPR1/2 (A. thaliana) A. thaliana, Zea mays, S. lycopersicum, Oryza sativa
PIP1/2 11-aa peptides Apoplastic preproPIP1/2 RLK7 A. thaliana
GmPep914/890 8-aa peptide Apoplastic or cytoplasmic GmproPep914/890 Unknown G. max
Zip1 17-aa peptide Apoplastic PROZIP1 Unknown Z. mays
IDL6p 11-aa peptide Apoplastic or cytoplasmic IDL6 precursors HEA/HSL2 A. thaliana
RALFs ~50-aa cysteine-rich peptides Apoplastic or cytoplasmic RALF precursors FER (A. thaliana) A. thaliana, N. tabacum, S. lycopersicum
PSKs 5-aa peptides Apoplastic or cytoplasmic PSK precursors PSKR1/2 (A. thaliana) A. thaliana, S. lycopersicum
HMGB3 HMGB3 protein Cytosolic and nuclear HMGB3 Unknown A. thaliana
Inceptin 11-aa peptide Chloroplastic ATP synthase γ-subunit Unknown Vigna unguiculata
Extracellular nucleotides eATP ATP Cytosolic ATP DORN1/P2K1 (A. thaliana) A. thaliana, N. tabacum
eNAD(P) NAD(P) Cytosolic NAD(P) LecRK-I.8 A. thaliana
eDNA DNA fragments < 700 bp in length Cytosolic and nuclear DNA Unknown Phaseolus vulgaris, P. lunatus, Pisum sativum, Z. mays
Extracellular sugars Extracellular sugars Sucrose, glucose, fructose, maltose Cytosolic sugars RGS1 (A. thaliana) A. thaliana, N. tabacum, Solanum tuberosum
Extracellular amino acids and glutathione Proteinogenic amino acids Glutamate, cysteine, histidine, aspartic acid Cytosolic amino acids GLR3.3/3.6 or others (A. thaliana) A. thaliana, S. lycopersicum, Oryza sativa
Glutathione Glutathione Cytosolic glutathione GLR3.3/3.6 (A. thaliana) A. thaliana

Many mammalian DAMPs have DAMP counterparts in plants. One example is with the high-mobility group protein. Mammals have the HMGB1 protein, while Arabidopsis thaliana has the HMGB3 protein.[37]

Clinical targets in various disorders

Preventing the release of DAMPs and blocking DAMP receptors would, in theory, stop inflammation from an injury or infection and reduce pain for the affected individual.[38] This is especially important during surgeries, which have the potential to trigger these inflammation pathways, making the surgery more difficult and dangerous to complete. The blocking of DAMPs also has theoretical applications in therapeutics to treat disorders such as arthritis, cancer, ischemia reperfusion, myocardial infarction, and stroke.[38] These theoretical therapeutic options include:

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

DAMPs can be used as biomarkers for inflammatory diseases and potential therapeutic targets. For example, increased S100A8/A9 is associated with osteophyte progression in early human osteoarthritis, suggesting that S100 proteins can be used as biomarkers for the diagnosis of the progressive grade of osteoarthritis.[39] Furthermore, DAMP can be a useful prognostic factor for cancer. This would improve patient classification, and a suitable therapy would be given to patients by diagnosing with DAMPs. The regulation of DAMP signaling can be a potential therapeutic target to reduce inflammation and treat diseases. For example, administration of neutralizing HMGB1 antibodies or truncated HMGB1-derived A-box protein ameliorated arthritis in collagen-induced arthritis rodent models. Clinical trials with HSP inhibitors have also been reported. For nonsmall-cell lung cancer, HSP27, HSP70, and HSP90 inhibitors are under investigation in clinical trials. In addition, treatment with dnaJP1, which is a synthetic peptide derived from DnaJ (HSP40), had a curative effect in rheumatoid arthritis patients without critical side effects. Taken together, DAMPs can be useful therapeutic targets for various human diseases, including cancer and autoimmune diseases.[3]

DAMPs can trigger re-epithelialization upon kidney injury, contributing to epithelial–mesenchymal transition, and potentially, to myofibroblast differentiation and proliferation. These discoveries suggest that DAMPs drive not only immune injury, but also kidney regeneration and renal scarring. For example, TLR2-agonistic DAMPs activate renal progenitor cells to regenerate epithelial defects in injured tubules. TLR4-agonistic DAMPs also induce renal dendritic cells to release IL-22, which also accelerates tubule re-epithelialization in acute kidney injury. Finally, DAMPs also promote renal fibrosis by inducing NLRP3, which also promotes TGF-β receptor signaling.[40]

References

  1. ↑ 1.0 1.1 "Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses". Nature Reviews. Immunology 4 (6): 469–78. June 2004. doi:10.1038/nri1372. PMID 15173835. 
  2. ↑ 2.0 2.1 "PAMPs and DAMPs: signal 0s that spur autophagy and immunity". Immunological Reviews 249 (1): 158–75. September 2012. doi:10.1111/j.1600-065X.2012.01146.x. PMID 22889221. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Damage-Associated Molecular Patterns in Inflammatory Diseases" (in English). Immune Network 18 (4): e27. August 2018. doi:10.4110/in.2018.18.e27. PMID 30181915. 
  4. ↑ "Damage-Associated Molecular Patterns in Inflammatory Diseases". Immune Network 18 (4): e27. August 2018. doi:10.4110/in.2018.18.e27. PMID 30181915. 
  5. ↑ "Inflammatory responses and inflammation-associated diseases in organs". Oncotarget 9 (6): 7204–7218. January 2018. doi:10.18632/oncotarget.23208. PMID 29467962. 
  6. ↑ "Immunogenicity signals 1,2,3 ... and 0". Immunology Today 10 (9): 283–6. September 1989. doi:10.1016/0167-5699(89)90081-9. PMID 2590379. 
  7. ↑ 7.0 7.1 "Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox". Trends in Immunology 28 (10): 429–36. October 2007. doi:10.1016/j.it.2007.08.004. PMID 17845865. 
  8. ↑ "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. January 1994. doi:10.1097/00007890-199401001-00010. PMID 8310510. 
  9. ↑ "Cell biology of ischemia/reperfusion injury". International Review of Cell and Molecular Biology 298: 229–317. 2012. doi:10.1016/B978-0-12-394309-5.00006-7. ISBN 9780123943095. PMID 22878108. 
  10. ↑ "Tolerance, danger, and the extended family". Annual Review of Immunology 12: 991–1045. 1994. doi:10.1146/annurev.iy.12.040194.005015. PMID 8011301. 
  11. ↑ "Stress cytokines: pivotal proteins in immune regulatory networks; Opinion". Current Opinion in Immunology 16 (4): 531–4. August 2004. doi:10.1016/j.coi.2004.05.017. PMID 15245751. 
  12. ↑ 12.0 12.1 "Release of chromatin protein HMGB1 by necrotic cells triggers inflammation". Nature 418 (6894): 191–5. July 2002. doi:10.1038/nature00858. PMID 12110890. 
  13. ↑ "Hyaluronan fragments act as an endogenous danger signal by engaging TLR2". Journal of Immunology 177 (2): 1272–81. July 2006. doi:10.4049/jimmunol.177.2.1272. PMID 16818787. 
  14. ↑ "Modulation of inflammation by extracellular nucleotides". The Journal of Investigative Dermatology 126 (5): 943–4. May 2006. doi:10.1038/sj.jid.5700233. PMID 16619009. 
  15. ↑ "Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation". Pharmacology & Therapeutics 112 (2): 358–404. November 2006. doi:10.1016/j.pharmthera.2005.04.013. PMID 16784779. 
  16. ↑ "Molecular identification of a danger signal that alerts the immune system to dying cells". Nature 425 (6957): 516–21. October 2003. doi:10.1038/nature01991. PMID 14520412. Bibcode: 2003Natur.425..516S. 
  17. ↑ "Detecting DNA: getting and begetting cancer". Current Opinion in Investigational Drugs 8 (12): 981–6. December 2007. PMID 18058568. 
  18. ↑ "The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway". EMBO Reports 3 (10): 995–1001. October 2002. doi:10.1093/embo-reports/kvf198. PMID 12231511. 
  19. ↑ "HMG-1 as a late mediator of endotoxin lethality in mice". Science 285 (5425): 248–51. July 1999. doi:10.1126/science.285.5425.248. PMID 10398600. 
  20. ↑ 20.0 20.1 "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology 56 (4): 739–44. December 2013. doi:10.1016/j.molimm.2013.07.008. PMID 23954397. 
  21. ↑ "Role of ROS and HMGB1 in contact allergen-induced IL-18 production in human keratinocytes". The Journal of Investigative Dermatology 134 (11): 2719–2727. November 2014. doi:10.1038/jid.2014.203. PMID 24780928. 
  22. ↑ 22.0 22.1 "Role of the microbiota in immunity and inflammation". Cell 157 (1): 121–41. March 2014. doi:10.1016/j.cell.2014.03.011. PMID 24679531. 
  23. ↑ "Ultraviolet radiation damages self noncoding RNA and is detected by TLR3". Nature Medicine 18 (8): 1286–90. August 2012. doi:10.1038/nm.2861. PMID 22772463. 
  24. ↑ "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. August 2004. doi:10.1158/0008-5472.CAN-04-2004. PMID 15313892. 
  25. ↑ "S100A7 and the progression of breast cancer". Breast Cancer Research 6 (4): 153–9. 2004. doi:10.1186/bcr816. PMID 15217486. 
  26. ↑ "S100 proteins and their influence on pro-survival pathways in cancer". Biochemistry and Cell Biology 82 (4): 508–15. August 2004. doi:10.1139/o04-052. PMID 15284904. 
  27. ↑ "Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells". The Journal of Biological Chemistry 279 (32): 34071–7. August 2004. doi:10.1074/jbc.M405419200. PMID 15178678. 
  28. ↑ "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. October 2004. doi:10.1016/j.bbrc.2004.07.096. PMID 15336958. 
  29. ↑ 29.0 29.1 "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review". Journal of Autoimmunity 57: 1–13. February 2015. doi:10.1016/j.jaut.2014.12.002. PMID 25578468. 
  30. ↑ 30.0 30.1 "Immune Surveillance of the CNS following Infection and Injury". Trends in Immunology 36 (10): 637–650. October 2015. doi:10.1016/j.it.2015.08.002. PMID 26431941. 
  31. ↑ "Addicted to death: invasive cancer and the immune response to unscheduled cell death". Journal of Immunotherapy 28 (1): 1–9. 2005. doi:10.1097/00002371-200501000-00001. PMID 15614039. 
  32. ↑ "New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development". Experimental & Molecular Medicine 46 (3): e83. March 2014. doi:10.1038/emm.2014.7. PMID 24626169. 
  33. ↑ "Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors". Nature Communications 3: 1034. 2012. doi:10.1038/ncomms2023. PMID 22948816. Bibcode: 2012NatCo...3.1034K. 
  34. ↑ "Extracellular DAMPs in Plants and Mammals: Immunity, Tissue Damage and Repair" (in English). Trends in Immunology 39 (11): 937–950. November 2018. doi:10.1016/j.it.2018.09.006. PMID 30293747. 
  35. ↑ 35.0 35.1 "DAMPs, MAMPs, and NAMPs in plant innate immunity". BMC Plant Biology 16 (1): 232. October 2016. doi:10.1186/s12870-016-0921-2. PMID 27782807. 
  36. ↑ "Damage-Associated Molecular Pattern-Triggered Immunity in Plants". Frontiers in Plant Science 10: 646. 2019-05-22. doi:10.3389/fpls.2019.00646. PMID 31191574. 
  37. ↑ "DAMPs, MAMPs, and NAMPs in plant innate immunity". BMC Plant Biology 16 (1): 232. October 2016. doi:10.1186/s12870-016-0921-2. PMID 27782807. 
  38. ↑ 38.0 38.1 "Blocking DAMPs but not PAMPs". Science Signaling 8 (360): ec13. 2015-01-20. doi:10.1126/scisignal.aaa6950. 
  39. ↑ "S100 Proteins As an Important Regulator of Macrophage Inflammation" (in English). Frontiers in Immunology 8: 1908. 2018. doi:10.3389/fimmu.2017.01908. PMID 29379499. 
  40. ↑ "Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis". Journal of the American Society of Nephrology 25 (7): 1387–400. July 2014. doi:10.1681/ASN.2014010117. PMID 24762401. 

Further reading



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Damage-associated_molecular_pattern&oldid=3648904"