View source for Damage-associated molecular pattern

{{short description|Type of molecules within cells}}
{{redirect|Danger signal|animal signaling|Aposematism|the 1945 film|Danger Signal}}
'''Damage-associated molecular patterns''' ('''DAMPs''')<ref name=pmid15173835>{{cite journal | vauthors = Seong SY, Matzinger P | title = Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses | journal = Nature Reviews. Immunology | volume = 4 | issue = 6 | pages = 469–78 | date = June 2004 | pmid = 15173835 | doi = 10.1038/nri1372 | s2cid = 13336660 }}</ref> are molecules within cells that are a component of the [[Innate immune system|innate immune response]] released from damaged or dying cells due to trauma or an infection by a [[pathogen]].<ref name=":1">{{cite journal | vauthors = Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT | title = PAMPs and DAMPs: signal 0s that spur autophagy and immunity | journal = Immunological Reviews | volume = 249 | issue = 1 | pages = 158–75 | date = September 2012 | pmid = 22889221 | pmc = 3662247 | doi = 10.1111/j.1600-065X.2012.01146.x }}</ref> 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.<ref name=":0">{{cite journal | vauthors = Roh JS, Sohn DH | title = Damage-Associated Molecular Patterns in Inflammatory Diseases | language = English | journal = Immune Network | volume = 18 | issue = 4 | pages = e27 | date = August 2018 | pmid = 30181915 | pmc = 6117512 | doi = 10.4110/in.2018.18.e27 }}</ref> Once a DAMP is released from the cell, it promotes a noninfectious [[inflammatory response]] by binding to a [[pattern recognition receptor]] (PRR).<ref>{{cite journal | vauthors = Roh JS, Sohn DH | title = Damage-Associated Molecular Patterns in Inflammatory Diseases | journal = Immune Network | volume = 18 | issue = 4 | pages = e27 | date = August 2018 | pmid = 30181915 | pmc = 6117512 | doi = 10.4110/in.2018.18.e27 }}</ref> 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.<ref>{{cite journal | vauthors = Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L | display-authors = 6 | title = Inflammatory responses and inflammation-associated diseases in organs | journal = Oncotarget | volume = 9 | issue = 6 | pages = 7204–7218 | date = January 2018 | pmid = 29467962 | pmc = 5805548 | doi = 10.18632/oncotarget.23208 }}</ref> As an example, the [[cytokine]] [[IL1A|IL-1α]] is a DAMP that originates within the [[Cell nucleus|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.<ref name=":0" /> In contrast to the noninfectious inflammatory response produced by DAMPs, [[pathogen-associated molecular pattern]]s (PAMPs) initiate and perpetuate the ''infectious'' pathogen-induced inflammatory response.<ref name="pmid2590379">{{cite journal | vauthors = Janeway C | title = Immunogenicity signals 1,2,3 ... and 0 | journal = Immunology Today | volume = 10 | issue = 9 | pages = 283–6 | date = September 1989 | pmid = 2590379 | doi = 10.1016/0167-5699(89)90081-9 }}</ref> Many DAMPs are nuclear or [[cytosol]]ic proteins with defined [[intracellular]] function that are released outside the cell following tissue injury.<ref name="pmid17845865" /> This displacement from the [[intracellular space]] to the extracellular space  moves the DAMPs from a [[Redox|reducing]] to an [[Redox|oxidizing]] environment, causing their functional [[Denaturation (biochemistry)|denaturation]], resulting in their loss of function.<ref name="pmid17845865">{{cite journal | vauthors = Rubartelli A, Lotze MT | title = Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox | journal = Trends in Immunology | volume = 28 | issue = 10 | pages = 429–36 | date = October 2007 | pmid = 17845865 | doi = 10.1016/j.it.2007.08.004 }}</ref> Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as [[Mitochondrion|mitochondria]], [[Granule (cell biology)|granules]], the [[extracellular matrix]], the [[endoplasmic reticulum]], and the [[plasma membrane]].<ref name=":0" />
==Overview==
DAMPs and their receptors are characterized as:<ref name=":0" />
{| class="wikitable"
|+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 (receptor)|RAGE]]
|-
|
|
|[[Heat-shock proteins]]
|[[TLR2]], [[TLR4]], [[CD91]]
|-
|
|
|[[Adenosine triphosphate|ATP]]
|[[P2X7]], [[P2Y2]]
|-
|
|
|[[F-actin]]
|[https://pubmed.ncbi.nlm.nih.gov/32117205/ DNGR-1]
|-
|
|
|[[Cyclophilin A]]
|[[CD147]]
|-
|
|
|[[Aβ]]
|[[TLR2]], [[NLRP1]], [[NLRP3]], [[CD36]], [[RAGE (receptor)|RAGE]]
|-
|
|[[Cell nucleus|Nuclear]]
|[[Histones]]
|[[TLR2]], [[TLR4]]
|-
|
|
|[[HMGB1]]
|[[TLR2]], [[TLR4]], [[RAGE (receptor)|RAGE]]
|-
|
|
|[[HMGN1]]
|[[TLR4]]
|-
|
|
|[[IL-1α]]
|[[IL-1R]]
|-
|
|
|[[IL-33]]
|[[IL1RL1|ST2]]
|-
|
|
|[[SAP130]]
|[[Mincle]]
|-
|
|
|[[DNA]]
|[[TLR9]], [[AIM2]]
|-
|
|
|[[RNA]]
|[[TLR3]], [[TLR7]], [[TLR8]], [[RIG-I]], [[MDA5]]
|-
|
|[[Mitochondria]]
|[[mtDNA]]
|[[TLR9]]
|-
|
|
|[[TFAM]]
|[[RAGE (receptor)|RAGE]]
|-
|
|
|[[Formyl peptide]]
|[[FPR1]]
|-
|
|
|[[Mitochondrial ROS|mROS]]
|[[NLRP3]]
|-
|
|[[Endoplasmic reticulum]]
|[[Calreticulin]]
|[[CD91]]
|-
|
|[[Vesicle (biology and chemistry)#Secretory vesicles|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<ref name=pmid8310510>{{cite journal | vauthors = Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, Arfors KE, Messmer K | display-authors = 6 | title = The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants | journal = Transplantation | volume = 57 | issue = 2 | pages = 211–7 | date = January 1994 | pmid = 8310510 | doi = 10.1097/00007890-199401001-00010 | doi-access = free }}</ref> 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 [[Kidney transplantation#Deceased donors|cadaveric renal allografts]] demonstrated prolonged patient and graft survival with improvement in both acute and chronic [[organ rejection|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.<ref>{{cite journal | vauthors = Kalogeris T, Baines CP, Krenz M, Korthuis RJ | title = Cell biology of ischemia/reperfusion injury | journal = International Review of Cell and Molecular Biology | volume = 298 | pages = 229–317 | date = 2012 | pmid = 22878108 | pmc = 3904795 | doi = 10.1016/B978-0-12-394309-5.00006-7 | isbn = 9780123943095 }}</ref>
The second study<ref name=pmid8011301>{{cite journal | vauthors = Matzinger P | title = Tolerance, danger, and the extended family | journal = Annual Review of Immunology | volume = 12 | pages = 991–1045 | year = 1994 | pmid = 8011301 | doi = 10.1146/annurev.iy.12.040194.005015 }}</ref>  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 feedback|positive]] and [[negative feedback|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.<ref name=pmid15173835/>
==Examples==
DAMPs vary greatly depending on the type of cell ([[Epithelium|epithelial]] or [[Mesenchyme|mesenchymal]]) and injured tissue, but they all share the common feature of stimulating an innate immune response within an organism.<ref name=":1" />
* Protein DAMPs include intracellular proteins, such as [[heat-shock proteins]]<ref name="pmid15245751">{{cite journal | vauthors = Panayi GS, Corrigall VM, Henderson B | title = Stress cytokines: pivotal proteins in immune regulatory networks; Opinion | journal = Current Opinion in Immunology | volume = 16 | issue = 4 | pages = 531–4 | date = August 2004 | pmid = 15245751 | doi = 10.1016/j.coi.2004.05.017 }}</ref> or [[HMGB1]],<ref name="pmid12110890">{{cite journal | vauthors = Scaffidi P, Misteli T, Bianchi ME | title = Release of chromatin protein HMGB1 by necrotic cells triggers inflammation | journal = Nature | volume = 418 | issue = 6894 | pages = 191–5 | date = July 2002 | pmid = 12110890 | doi = 10.1038/nature00858 | s2cid = 4403741 }}</ref> and materials derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments.<ref name="pmid16818787">{{cite journal | vauthors = Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR | title = Hyaluronan fragments act as an endogenous danger signal by engaging TLR2 | journal = Journal of Immunology | volume = 177 | issue = 2 | pages = 1272–81 | date = July 2006 | pmid = 16818787 | doi = 10.4049/jimmunol.177.2.1272 | doi-access = free }}</ref>
* Non-protein DAMPs include ATP,<ref name="pmi16619009">{{cite journal | vauthors = Boeynaems JM, Communi D | title = Modulation of inflammation by extracellular nucleotides | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 5 | pages = 943–4 | date = May 2006 | pmid = 16619009 | doi = 10.1038/sj.jid.5700233 | doi-access = free }}</ref><ref name="pmid16784779">{{cite journal | vauthors = Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC | title = Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation | journal = Pharmacology & Therapeutics | volume = 112 | issue = 2 | pages = 358–404 | date = November 2006 | pmid = 16784779 | doi = 10.1016/j.pharmthera.2005.04.013 }}</ref> uric acid,<ref name="pmid14520412">{{cite journal | vauthors = Shi Y, Evans JE, Rock KL | title = Molecular identification of a danger signal that alerts the immune system to dying cells | journal = Nature | volume = 425 | issue = 6957 | pages = 516–21 | date = October 2003 | pmid = 14520412 | doi = 10.1038/nature01991 | s2cid = 2150167 | bibcode = 2003Natur.425..516S }}</ref> heparin sulfate and DNA.<ref name="pmid18058568">{{cite journal | vauthors = Farkas AM, Kilgore TM, Lotze MT | title = Detecting DNA: getting and begetting cancer | journal = Current Opinion in Investigational Drugs | volume = 8 | issue = 12 | pages = 981–6 | date = December 2007 | pmid = 18058568 }}</ref>
=== In humans ===
==== Protein DAMPs ====
# [[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 cell]]s through a [[lysosome]]-mediated pathway.<ref name="pmid12231511">{{cite journal | vauthors = Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A | title = The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway | journal = EMBO Reports | volume = 3 | issue = 10 | pages = 995–1001 | date = October 2002 | pmid = 12231511 | pmc = 1307617 | doi = 10.1093/embo-reports/kvf198 }}</ref> HMGB1 is a major mediator of [[endotoxin]] shock<ref name="pmid10398600">{{cite journal | vauthors = 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 | display-authors = 6 | title = HMG-1 as a late mediator of endotoxin lethality in mice | journal = Science | volume = 285 | issue = 5425 | pages = 248–51 | date = July 1999 | pmid = 10398600 | doi = 10.1126/science.285.5425.248 }}</ref> and is recognized as a DAMP by certain immune cells, triggering an inflammatory response.<ref name="pmid12110890" /> It is known to induce inflammation by activating [[NF-κB]] pathway by binding to TLR, TLR4, TLR9, and RAGE (receptor for advanced glycation end products).<ref name="pmid23954397">{{cite journal | vauthors = Ibrahim ZA, Armour CL, Phipps S, Sukkar MB | title = RAGE and TLRs: relatives, friends or neighbours? | journal = Molecular Immunology | volume = 56 | issue = 4 | pages = 739–44 | date = December 2013 | pmid = 23954397 | doi = 10.1016/j.molimm.2013.07.008 }}</ref> 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 molecule]]s (ICAM-1, VCAM-1) on [[endothelial cells]].<ref>{{cite journal | vauthors = Galbiati V, Papale A, Galli CL, Marinovich M, Corsini E | title = Role of ROS and HMGB1 in contact allergen-induced IL-18 production in human keratinocytes | journal = The Journal of Investigative Dermatology | volume = 134 | issue = 11 | pages = 2719–2727 | date = November 2014 | pmid = 24780928 | doi = 10.1038/jid.2014.203 | doi-access = free }}</ref>
# DNA and RNA: The presence of DNA anywhere other than the [[Cell nucleus|nucleus]] or [[mitochondria]] is perceived as a DAMP and triggers responses mediated by [[TLR9]] and [[ZBP1|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.<ref name=":2">{{cite journal | vauthors = Belkaid Y, Hand TW | title = Role of the microbiota in immunity and inflammation | journal = Cell | volume = 157 | issue = 1 | pages = 121–41 | date = March 2014 | pmid = 24679531 | pmc = 4056765 | doi = 10.1016/j.cell.2014.03.011 }}</ref> Without being inhibited by DNA, the gut would detect these microbiota as invading pathogens, and initiate an 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.<ref name=":2" /> 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.<ref name="pmid22772463">{{cite journal | vauthors = Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, Martinez L, Greidinger EL, Yu BD, Gallo RL | display-authors = 6 | title = Ultraviolet radiation damages self noncoding RNA and is detected by TLR3 | journal = Nature Medicine | volume = 18 | issue = 8 | pages = 1286–90 | date = August 2012 | pmid = 22772463 | pmc = 3812946 | doi = 10.1038/nm.2861 }}</ref>
# S100 proteins: [[S100 protein|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.<ref name="pmid15313892">{{cite journal | vauthors = 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 | display-authors = 6 | title = S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer | journal = Cancer Research | volume = 64 | issue = 16 | pages = 5564–9 | date = August 2004 | pmid = 15313892 | doi = 10.1158/0008-5472.CAN-04-2004 | doi-access = free | url = https://aacr.figshare.com/articles/journal_contribution/Supplementary_Materials_from_S100_Family_Members_and_Trypsinogens_Are_Predictors_of_Distant_Metastasis_and_Survival_in_Early-Stage_Non-Small_Cell_Lung_Cancer/22363619/1/files/39807830.pdf }}</ref><ref name="pmid15217486">{{cite journal | vauthors = Emberley ED, Murphy LC, Watson PH | title = S100A7 and the progression of breast cancer | journal = Breast Cancer Research | volume = 6 | issue = 4 | pages = 153–9 | year = 2004 | pmid = 15217486 | pmc = 468668 | doi = 10.1186/bcr816 | doi-access = free }}</ref><ref name="pmid15284904">{{cite journal | vauthors = Emberley ED, Murphy LC, Watson PH | title = S100 proteins and their influence on pro-survival pathways in cancer | journal = Biochemistry and Cell Biology | volume = 82 | issue = 4 | pages = 508–15 | date = August 2004 | pmid = 15284904 | doi = 10.1139/o04-052 }}</ref><ref name="pmid15178678">{{cite journal | vauthors = Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F, Weber DJ | title = Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 32 | pages = 34071–7 | date = August 2004 | pmid = 15178678 | doi = 10.1074/jbc.M405419200 | doi-access = free }}</ref><ref name="pmid15336958">{{cite journal | vauthors = Marenholz I, Heizmann CW, Fritz G | title = S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature) | journal = Biochemical and Biophysical Research Communications | volume = 322 | issue = 4 | pages = 1111–22 | date = October 2004 | pmid = 15336958 | doi = 10.1016/j.bbrc.2004.07.096 }}</ref><ref name="pmid23954397" /> Their main function is the management of calcium storage and shuffling. Although they have various functions, including [[cell proliferation]], [[Cellular differentiation|differentiation]], [[Cellular migration|migration]], and [[energy metabolism]], they also act as DAMPs by interacting with their receptors (TLR2, TLR4, RAGE) after they are released from [[phagocyte]]s.<ref name=":0" />
# Mono- and polysaccharides: The ability of the immune system to recognize [[hyaluronan]] fragments is one example of how DAMPs can be made of sugars.<ref name="pmid25578468" />
==== Nonprotein DAMPs ====
*Purine metabolites: [[Nucleotide]]s (e.g., [[Adenosine triphosphate|ATP]]) and [[nucleoside]]s (e.g., [[adenosine]]) that have reached the extracellular space can also serve as ''danger'' signals by signaling through [[purinergic receptor]]s.<ref name="pmid26431941" /> ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in [[Necrosis|necrotic]] cell death.<ref name="pmid15614039">{{cite journal | vauthors = Zeh HJ, Lotze MT | title = Addicted to death: invasive cancer and the immune response to unscheduled cell death | journal = Journal of Immunotherapy | volume = 28 | issue = 1 | pages = 1–9 | year = 2005 | pmid = 15614039 | doi = 10.1097/00002371-200501000-00001 | s2cid = 31331291 }}</ref> Extracellular ATP triggers [[mast cell]] [[degranulation]] by signaling through [[P2X7]] receptors.<ref name="pmid24626169">{{cite journal | vauthors = Kurashima Y, Kiyono H | title = New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development | journal = Experimental & Molecular Medicine | volume = 46 | issue = 3 | pages = e83 | date = March 2014 | pmid = 24626169 | pmc = 3972796 | doi = 10.1038/emm.2014.7 }}</ref><ref name="pmid26431941">{{cite journal | vauthors = Russo MV, McGavern DB | title = Immune Surveillance of the CNS following Infection and Injury | journal = Trends in Immunology | volume = 36 | issue = 10 | pages = 637–650 | date = October 2015 | pmid = 26431941 | pmc = 4592776 | doi = 10.1016/j.it.2015.08.002 }}</ref><ref name="pmid22948816">{{cite journal | vauthors = 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 | display-authors = 6 | title = Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors | journal = Nature Communications | volume = 3 | pages = 1034 | year = 2012 | pmid = 22948816 | pmc = 3658010 | doi = 10.1038/ncomms2023 | bibcode = 2012NatCo...3.1034K }}</ref> Similarly, adenosine triggers degranulation through [[P1 receptors]]. [[Uric acid]] is also an endogenous danger signal released by injured cells.<ref name="pmid25578468">{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | display-authors = 6 | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}</ref> 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.<ref name=":0" />
=== In plants ===
DAMPs in plants have been found to stimulate a fast immune response, but without the inflammation that characterizes DAMPs in mammals.<ref>{{cite journal | vauthors = De Lorenzo G, Ferrari S, Cervone F, Okun E | title = Extracellular DAMPs in Plants and Mammals: Immunity, Tissue Damage and Repair | language = English | journal = Trends in Immunology | volume = 39 | issue = 11 | pages = 937–950 | date = November 2018 | pmid = 30293747 | doi = 10.1016/j.it.2018.09.006 | s2cid = 52927468 }}</ref> 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.<ref name=":4" /> 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 [[Pathogen-associated molecular pattern|PAMPs]] to initiate signaling throughout the plant that damage has occurred 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.<ref>{{cite journal | vauthors = Hou S, Liu Z, Shen H, Wu D | title = Damage-Associated Molecular Pattern-Triggered Immunity in Plants | journal = Frontiers in Plant Science | volume = 10 | pages = 646 | date = 2019-05-22 | pmid = 31191574 | pmc = 6547358 | doi = 10.3389/fpls.2019.00646 | doi-access = free }}</ref>
Plant DAMPs and their receptors are characterized as:<ref name=":4">{{cite journal | vauthors = Choi HW, Klessig DF | title = DAMPs, MAMPs, and NAMPs in plant innate immunity | journal = BMC Plant Biology | volume = 16 | issue = 1 | pages = 232 | date = October 2016 | pmid = 27782807 | doi = 10.1186/s12870-016-0921-2 | pmc = 5080799 | doi-access = free }}</ref>
{| class="wikitable"
|+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
|-
! rowspan=1 | Epidermis cuticle
|Cutin monomers
|C16 and C18 hydroxy and epoxy fatty acids
|Epidermis cuticle
| Unknown
|''Arabidopsis thaliana'', ''Solanum lycopersicum''
|-
! rowspan=4 | 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''
|-
! rowspan=14 | 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
|INR<ref>{{Cite journal |last1=Steinbrenner |first1=Adam D. |last2=Muñoz-Amatriaín |first2=Maria |last3=Chaparro |first3=Antonio F. |last4=Aguilar-Venegas |first4=Jessica Montserrat |last5=Lo |first5=Sassoum |last6=Okuda |first6=Satohiro |last7=Glauser |first7=Gaetan |last8=Dongiovanni |first8=Julien |last9=Shi |first9=Da |last10=Hall |first10=Marlo |last11=Crubaugh |first11=Daniel |last12=Holton |first12=Nicholas |last13=Zipfel |first13=Cyril |last14=Abagyan |first14=Ruben |last15=Turlings |first15=Ted C. J. |date=2020-12-08 |title=A receptor-like protein mediates plant immune responses to herbivore-associated molecular patterns |journal=Proceedings of the National Academy of Sciences |language=en |volume=117 |issue=49 |pages=31510–31518 |doi=10.1073/pnas.2018415117 |doi-access=free |issn=0027-8424 |pmc=7733821 |pmid=33229576|bibcode=2020PNAS..11731510S }}</ref>
|''Vigna unguiculata''
|-
! rowspan=3 | 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''
|-
! rowspan=2 | 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.<ref>{{cite journal|vauthors=Choi HW, Klessig DF|date=October 2016|title=DAMPs, MAMPs, and NAMPs in plant innate immunity|journal=BMC Plant Biology|volume=16|issue=1|pages=232|doi=10.1186/s12870-016-0921-2|pmc=5080799|pmid=27782807 |doi-access=free }}</ref>
==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.<ref name=":3">{{cite journal| vauthors = Foley JF |date=2015-01-20|title=Blocking DAMPs but not PAMPs |journal=Science Signaling |volume=8 |issue=360 |pages=ec13 |doi=10.1126/scisignal.aaa6950 |s2cid=51601795 }}</ref> 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 injury of the appendicular musculoskeletal system|ischemia reperfusion]], [[myocardial infarction]], and [[stroke]].<ref name=":3" /> These theoretical therapeutic options include:
*Preventing DAMP release – proapoptotic therapies, platinums, [[ethyl pyruvate]]
*Neutralizing or blocking DAMPs extracellularly – anti-HMGB1, rasburicase, {{not a typo|sRAGE}}, etc.
*Blocking the DAMP receptors or their signaling – [[RAGE (receptor)|RAGE]] small molecule antagonists, TLR4 antagonists, antibodies to DAMP-R
DAMPs can be used as [[biomarker]]s for inflammatory diseases and potential therapeutic targets. For example, increased S100A8/A9 is associated with [[osteophyte]] progression in early human  [[osteoarthritis]], suggesting that [[S100 protein]]s can be used as biomarkers for the diagnosis of the progressive grade of osteoarthritis.<ref>{{cite journal | vauthors = Xia C, Braunstein Z, Toomey AC, Zhong J, Rao X | title = S100 Proteins As an Important Regulator of Macrophage Inflammation | language = English | journal = Frontiers in Immunology | volume = 8 | pages = 1908 | date = 2018 | pmid = 29379499 | doi = 10.3389/fimmu.2017.01908 | pmc = 5770888 | doi-access = free }}</ref> 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 [[Non-small-cell lung carcinoma|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.<ref name=":0" />
DAMPs can trigger [[Wound healing|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.<ref>{{cite journal | vauthors = Anders HJ, Schaefer L | title = Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis | journal = Journal of the American Society of Nephrology | volume = 25 | issue = 7 | pages = 1387–400 | date = July 2014 | pmid = 24762401 | pmc = 4073442 | doi = 10.1681/ASN.2014010117 }}</ref>
== References ==
{{reflist|32em}}
== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Kaczmarek A, Vandenabeele P, Krysko DV | title = Necroptosis: the release of damage-associated molecular patterns and its physiological relevance | journal = Immunity | volume = 38 | issue = 2 | pages = 209–23 | date = February 2013 | pmid = 23438821 | doi = 10.1016/j.immuni.2013.02.003 | doi-access = free }}
* {{cite journal | vauthors = Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P | title = Immunogenic cell death and DAMPs in cancer therapy | journal = Nature Reviews. Cancer | volume = 12 | issue = 12 | pages = 860–75 | date = December 2012 | pmid = 23151605 | doi = 10.1038/nrc3380 | s2cid = 223813 }}
* {{cite journal | vauthors = Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P | title = Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1805 | issue = 1 | pages = 53–71 | date = January 2010 | pmid = 19720113 | doi = 10.1016/j.bbcan.2009.08.003 | url = https://lirias.kuleuven.be/bitstream/123456789/632508/2/BBA-RC%20Review%20-%20Final%20Revised%20MS.doc }}
* {{cite journal | vauthors = Garg AD, Krysko DV, Vandenabeele P, Agostinis P | title = DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown | journal = Photochemical & Photobiological Sciences | volume = 10 | issue = 5 | pages = 670–80 | date = May 2011 | pmid = 21258717 | doi = 10.1039/C0PP00294A | bibcode = 2011PhPhS..10..670G | url = https://biblio.ugent.be/publication/1224416 | hdl = 1854/LU-1224416 | hdl-access = free }}
* {{cite journal | vauthors = Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P | title = Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation | journal = Trends in Immunology | volume = 32 | issue = 4 | pages = 157–64 | date = April 2011 | pmid = 21334975 | doi = 10.1016/j.it.2011.01.005 | url = https://lirias.kuleuven.be/bitstream/123456789/632510/2/Krysko%20et%20al%20_21-09-10.doc }}
*[https://web.archive.org/web/20100709223644/http://www.damp.pitt.edu/index.html Damage Associated Molecular Pattern Molecules Group] at University of Pittsburgh
* {{cite journal | vauthors = Lotze MT, Deisseroth A, Rubartelli A | title = Damage associated molecular pattern molecules | journal = Clinical Immunology | volume = 124 | issue = 1 | pages = 1–4 | date = July 2007 | pmid = 17468050 | pmc = 2000827 | doi = 10.1016/j.clim.2007.02.006 }}
* {{cite journal | vauthors = Lotze MT, Tracey KJ | title = High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal | journal = Nature Reviews. Immunology | volume = 5 | issue = 4 | pages = 331–42 | date = April 2005 | pmid = 15803152 | doi = 10.1038/nri1594 | s2cid = 27691169 }}
* {{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | display-authors = 6 | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}
{{refend}}
{{DEFAULTSORT:Damps}}
[[Category:Immunology]]