Damage-associated molecular pattern
Damage-associated molecular patterns (DAMPs)
Overview
DAMPs and their receptors are characterized as:[3]
Origin | Major DAMPs | Receptors | |
---|---|---|---|
Extracellular matrix | Biglycan | TLR4, NLRP3
| |
Decorin | TLR4
| ||
Versican | TLR6, CD14
| ||
LMW hyaluronan
|
TLR4, NLRP3
| ||
Heparan sulfate | TLR4
| ||
Fibronectin (EDA domain) | TLR4
| ||
Fibrinogen | TLR4
| ||
Tenascin C | TLR4
| ||
Intracellular compartments
|
Cytosol | Uric Acid
|
P2X7
|
S100 proteins
|
TLR4, RAGE
| ||
Heat-shock proteins
|
CD91
| ||
ATP | P2Y2
| ||
F-actin
|
DNGR-1 | ||
Cyclophilin A
|
CD147
| ||
Aβ
|
|||
Nuclear | Histones
|
TLR4
| |
HMGB1 | TLR4, RAGE
| ||
HMGN1 | TLR4
| ||
IL-1α
|
IL-1R
| ||
IL-33
|
ST2 | ||
SAP130 | Mincle
| ||
DNA | TLR9, AIM2
| ||
RNA | |||
Mitochondria
|
mtDNA
|
TLR9
| |
TFAM | RAGE | ||
Formyl peptide
|
FPR1
| ||
mROS | NLRP3 | ||
Endoplasmic reticulum | Calreticulin | CD91
| |
Granule | Defensins
|
TLR4
| |
Cathelicidin (LL37)
|
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
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
- Non-protein DAMPs include ATP,[14][15] uric acid,[16] heparin sulfate and DNA.[17]
In humans
Protein DAMPs
- High-mobility group box 1: HMGB1, a member of the HMG protein family, is a prototypical endothelial cells.[21]
- DNA and RNA: The presence of DNA anywhere other than the 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]
- S100 proteins: energy metabolism, they also act as DAMPs by interacting with their receptors (TLR2, TLR4, RAGE) after they are released from phagocytes.[3]
- 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:
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]
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
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]
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Further reading
- Kaczmarek A, Vandenabeele P, Krysko DV (February 2013). "Necroptosis: the release of damage-associated molecular patterns and its physiological relevance". Immunity. 38 (2): 209–23. PMID 23438821.
- Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P (December 2012). "Immunogenic cell death and DAMPs in cancer therapy". Nature Reviews. Cancer. 12 (12): 860–75. S2CID 223813.
- Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P (January 2010). "Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation". Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. 1805 (1): 53–71. PMID 19720113.
- Garg AD, Krysko DV, Vandenabeele P, Agostinis P (May 2011). "DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown". Photochemical & Photobiological Sciences. 10 (5): 670–80. PMID 21258717.
- Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P (April 2011). "Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation". Trends in Immunology. 32 (4): 157–64. PMID 21334975.
- Damage Associated Molecular Pattern Molecules Group at University of Pittsburgh
- Lotze MT, Deisseroth A, Rubartelli A (July 2007). "Damage associated molecular pattern molecules". Clinical Immunology. 124 (1): 1–4. PMID 17468050.
- Lotze MT, Tracey KJ (April 2005). "High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal". Nature Reviews. Immunology. 5 (4): 331–42. S2CID 27691169.
- Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, et al. (February 2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review". Journal of Autoimmunity. 57: 1–13. PMID 25578468.