Types of Danger-Associated Molecular Patterns (DAMPs): History
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Subjects: Immunology
Contributor:
Esther Jumilla
,
María José Caballero-Herrero
,
Manuel Buitrago-Ruiz
,
Graciela Valero-Navarro
,
Santiago Cuevas

The innate system is primed to sense “danger signals”, described as damage-associated molecular patterns (DAMPs), and respond to them, usually by activating the immune system and creating a pro-inflammatory environment. These DAMPs are molecules that are inherent to the organism but have a high pro-inflammatory power when they are detected in places where they are not usually present, such as in extracellular or free-form contexts, which is an indicator of tissue damage and produced in surgical processes. DAMPs are molecules inherent to the organism, but which have a high proinflammatory power by activating the inflammasome when detected in places where they are not usually present, such as in extracellular contexts or in free form. The presence of DAMPs is an indicator of tissue damage and can be produced in surgical processes. 

  • damage-associated molecular patterns
  • anastomotic leak
  • NLRP3 inflammasome
  • DAMPs

1. Heat Shock Proteins (HSPs)

HSPs are a family of chaperones that maintain and minimize the damage caused by increased temperature and maintain cellular homeostasis. This type of protein is classified depending on its molecular weight in six families.
These proteins can be released into extracellular space passively by necrosis or actively via secretory vesicles or by binding to ATP-binding cassette (ABC) transporters, which are a group of proteins that use the energy of ATP hydrolysis to transport the molecule out of the cell[1]. HSP90 proteins, together with their co-chaperone SGT1, and HSP70, have an important role in the regulation of the NLRP3 inflammasome since they stabilize the inflammasome inside the cell and keep it inactive because the HSP90 protein associates with the NACHT and LRR domains. Nevertheless, when these proteins are released into the extracellular space, they activate the innate immune system response by binding to TLRs[2][3].
The extracellular HSP70 protein induces the activation of the immune system, increasing microbicide capacity and neutrophil chemotaxis and phagocytosis. It has also been observed to stimulate tumour cell growth and resistance to apoptosis. Oppositely, the HSP90 protein activates the motility of cancer cells, their migration and subsequent metastasis. It also promotes neuronal motility and wound healing[1].

2. High-Mobility Group Protein Box 1 (HMGB1)

HMGB1 is a non-histone nuclear protein that belongs to the HMGB family of proteins that binds to DNA in the nucleus and is required for transcription, gene regulation and DNA repair, and contributes to the maintenance of DNA structure[4]. The liberation of HMGB1 into extracellular space is regulated by several factors, such as oxidative stress, N-glycosylation of three residues of the protein, and ADP-ribosylation at the carboxyl-terminal end of the molecule[4].
It can be released by passive or active release. However, it is not released via the classical endoplasmic reticulum–Golgi complex pathway[5]. The most studied release models correspond to active release. One of them consists of the activation of target cells that will subsequently release HMGB1. On the other hand, the second method studied consists of the packaging of the molecule into vesicles, such as lysosomes, and its release into the extracellular space, release through lysosomes can be triggered by cytokines, signalling pathways, such as STAT or the NF-𝜅β pathway, and cell–cell interactions[4]. The HMGB1 molecule can bind to multiple receptors (RAGE, TLR4, TLR2, TLR9, etc.) causing the continuous release of cytokines and chemokines and, thus, the constant activation of the immune system[6].

3. Adenosine Triphosphate (ATP)

ATP is the energy carrier molecule for all living things; however, when it is liberated into extracellular space, it acts as DAMP. ATP can be released passively in damaged tissues or cells undergoing apoptosis or pyroptosis. It can also be freed actively by two mechanisms, by exocytosis through vesicles and lysosomes or pores of the connexin and pannexin hemichannels[5]. Hemichannels open in response to various stimuli, for example, connexin is regulated by intracellular calcium concentrations, positive changes in plasma membrane voltage and phosphorylation of its serine residues, whereas exchange through pannexin is regulated by mechanical stress, increased intracellular calcium or potassium, and cleavage of the carboxyl-terminal end by caspase-3/caspase-7 and caspase-11 activated during apoptosis[5]. Binding of ATP to its receptors, P2X4R and P2X7R or P2X7, is a major stimulus for the activation of NLRP3 and NLRP1 inflammasome caspase-1. Binding of extracellular ATP to the P2X7R receptor causes its opening and the outflow of potassium into the cell. Moreover, the binding of ATP and the P2X4R receptor allows the recruitment of the pannexin hemichannel and the formation of a pore that causes the entry of extracellular material into the cell and the activation of the inflammasome. Other studies indicate that it is the high concentration of extracellular potassium that triggers inflammasome activation[7][8][9].

4. Uric Acid Crystals

The presence of uric acid has been associated with an influx of water that causes the cell to swell. This hyperosmolarity is associated with an increase in macrophage size and an intracellular decrease in potassium and chloride ions which, in turn, participates in the activation of NLRP3 (not being alone sufficient for its activation)[7].
The phagolysosomes formed by macrophages upon absorbing the crystals are unstable, thus stimulating their release into the cytosol; this liberation is accompanied by cathepsin B that induces NLRP3 activation[10].

5. Extracellular DNA

Extracellular DNA, mitochondrial or nuclear and free or associated with proteins, acts as DAMPs. The mechanism of release of these molecules is passively by cell death, necrosis, apoptosis, pyroptosis, etc. DNA can also be actively released through extracellular vesicles[5]. During apoptosis, mitochondrial DNA is liberated into the cytoplasm; it has been observed in those cells that mitochondria dysfunction leads to IL-1β secretion and activates the NLRP3 inflammasome[11]. In addition, there is positive feedback, when NLRP3 inflammasome activation occurs, through the outflow of intracellular potassium or the influx of extracellular calcium, plasma membrane rupture occurs and causes the release of mitochondrial DNA (mtDNA) and an increase in reactive oxygen species (ROS) that oxidize DNA. Mitochondria damage does not induce NLRP3 signalling if priming is omitted[12].
On the other hand, it has been observed that, despite the fact that NLRP3 is preferentially activated by mtDNA, AIM2, another type of is inflammasome, is activated by nuclear DNA[11]. In this case, the same happens as with NLRP3, cytoplasmic DNA interacts with ASC and activates caspase-1 to form the inflammasome[13]. Outside the cell, extracellular DNA damages neighbouring cells, mainly due to DNA bound to histones, which interacts with phosphate groups of phospholipids. In this case, NLRP3 activation occurs by inducing ROS, the outflow of potassium from the cell, and the entry of calcium into the cell. In addition, histone H4 can also activate TLR-2 and TLR-4 providing the necessary signals for inflammasome formation[13].

6. Fibronectin

It has another function different from the rest. Fibronectin is a glycoprotein that stimulates the release of irisin which confers cardioprotection against various pathological stimuli. It has been studied that fibronectin type III domain 5 downregulates NLRP3, ASC, and caspase-1, one of the reasons being the reduction of ROS generation required for NLRP3 activation[14].

7. Free Fatty Acids

Free fatty acids must also be considered DAMPs. It has been shown in several studies that fatty acid synthesis is involved in the activation of dendritic cells and differentiation of B lymphocytes and monocytes; it activates the immune system. Furthermore, obesity-induced danger signals, such as free fatty acids, bind to the TLR-4 receptor and induce the expression of proinflammatory cytokines and the expression of the NLRP3 inflammasome. Additionally, from free fatty acids, activation of the inflammasome occurs by the generation of mitochondrial ROS[15][16]. The imbalance between saturated and unsaturated fatty acids causes the intracellular crystallization of saturated fatty acids. On the other hand, the enzyme LDL oxidase promotes the formation of cholesterol crystals. Both crystals formed inside the cell or phagocytosed cause lysosomal destabilization, leading to the liberation of cathepsin B (involved in protein hydrolysis) which activates the NLRP3 inflammasome[16]. Inhibition of mitochondrial uncoupling protein 2 and thus fatty acid synthase enzyme (FASN), a lipogenic enzyme that promotes glucose-dependent fatty acid synthesis, was shown to suppress the expression of caspase-1, NLRP3 and pro-IL-1β[15].
A group of fatty acids that prevent inflammation is the resolvin family, which are molecules derived from the essential ω3 polyunsaturated fatty acids. It has been studied that resolvin, among others, could inhibit mechanical hypersensitivity and promote inflammatory resolution. It has been investigated that resolvin D2 (RvD2) was able to inhibit the NLRP3 inflammasome and observed that RvD2 promoted NLRP3 and IL-1β degradation through autophagy in macrophages, but it was dependent on the dose given[17][18]. Another fatty acid that also promotes the resolution of inflammation is the maresins, a family of fatty acids derived from docosahexaenoic acid. In several trials, it was observed to down-regulate the expression of cytokines, such as IL-1β, IL-18 and TNF-α. It was also seen to inhibit inflammasome activation and cell pyroptosis through the NF-𝜅β/p65 pathway[17].

8. Hyaluronic Acid

Short fragments of free hyaluronan are another DAMP that causes inflammasome activation; the production of this molecule is induced by ozone, producing airway hyperreactivity. Furthermore, hyaluronan causes cleavage and activation of pro-caspase-1, leading to activation of the inflammasome. On the other hand, hyaluronan production is related to IL-1β production and it has been shown that this hyaluronan-induced release of IL-1β is dependent on the NLRP3 inflammasome[19].
Table 1. Types of DAMP.
Name Origin Cellular Function Cellular Target That Activates the Inflammasome
Heat shock proteins (HSPs) They are proteins that originate in stressful situations for the cell They maintain an optimal temperature in the cell, participate in cell cycle control, and activate the immune system. TLR4[2][3]
High-mobility group protein Box 1 (HMGB1) They are non-histone nuclear proteins that enable transcriptional regulation Participate in DNA molecule stabilization, gene expression and activate the immune system Binds to receptors such as RAGE, TLR4, TLR2, TLR9 that produce cytokines and activate the immune system[6]
ATP These molecules are present in all cells and are indispensable for their correct functioning It releases energy when phosphoanhydride bonds are hydrolyzed Activates the inflammasome through the P2X4R and P2X7R receptors[2][8][9]
Uric Acid Crystals Compound formed in the body in the catabolism of purines Decreases nitric oxide, maintains the elasticity of blood vessels and promotes glucose absorption TLR2[10]
Extracellular DNA Molecule that contains the information necessary for the development and functioning of the organism DNA stores the information for building all cellular components Union of ASC molecules, TLR2 and TLR4[11][13]
Mitochondrial DNA It is the circular chromosome found within the mitochondria Encodes 5–10% of mitochondrial proteins Union of ASC molecules, TLR2 and TLR4[11][13]
Fibronectin Glycoprotein involved in the protection of cardiac muscle Enables the formation of fibrils in areas of tissue remodeling TLR4 and TLR2[14]
Free Fatty Acids They come from triglycerides, when lipolysis of adipose tissue occurs They act as a source of energy or precursors of other molecules TLR4[15][16]
Short fragments of free hyaluronan It is a compound synthesized by the cell membrane of all cells in the organism and is located in the extracellular matrix It is a key component for cell motility, adhesion and proliferation TLR2[19]
 

This entry is adapted from the peer-reviewed paper 10.3390/ijms24043862

References

  1. Extracellular heat shock proteins: A new location, a new function. . Pubmed. Retrieved 2023-3-1
  2. Inflammasome: Activation mechanisms . Pubmed. Retrieved 2023-3-1
  3. Galliussi, Germán. Mecanismos antiinflamatorios de los nitroalquenos :regulación del inflamasoma; Udelar FC: Univerdisas de la República, 2015; pp. 14.
  4. The mechanism of HMGB1 secretion and release . Experimental & Molecular Medicine. Retrieved 2023-3-1
  5. Release mechanisms of major DAMPs . Springer Link. Retrieved 2023-3-1
  6. Raúl Josué Rivera Pérez, María de la Luz Sevilla González, Javier Flores Estrada; Estrategias para inhibir a HMGB1 liberado durante la sepsis. Revista del Hospital Juárez de México 2016, 83, 142-147, .
  7. Inflammasome: activation mechanisms . Pubmed. Retrieved 2023-3-1
  8. ATP-Binding and Hydrolysis in Inflammasome Activation . MDPI. Retrieved 2023-3-1
  9. The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes . Journal of Biological Chemistry. Retrieved 2023-3-1
  10. The Role of Uric Acid as an Endogenous Danger Signal in Immunity and Inflammation . Springer Link. Retrieved 2023-3-1
  11. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis . ScienceDirect. Retrieved 2023-3-1
  12. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation . Nature. Retrieved 2023-3-1
  13. Inflammasome activation by nucleic acids and nucleosomes in sterile inflammation… or is it sterile? . Pubmed. Retrieved 2023-3-1
  14. Fibronectin type III domain-containing 5 improves aging-related cardiac dysfunction in mice . Wiley Online Library. Retrieved 2023-3-1
  15. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis . Pubmed. Retrieved 2023-3-1
  16. Saturated fatty acid-crystals activate NLRP3 inflammasome . Pubmed. Retrieved 2023-3-1
  17. Maresin 1 Attenuates Radicular Pain Through the Inhibition of NLRP3 Inflammasome-Induced Pyroptosis via NF-κB Signaling . Frontiers in Neuroscience. Retrieved 2023-3-1
  18. Resolvin D2 suppresses NLRP3 inflammasome by promoting autophagy in macrophages . Spandidos Publications. Retrieved 2023-3-1
  19. Hyaluronan Activation of the NLRP3 Inflammasome Contributes to the Development of Airway Hyperresponsiveness . Environmental Health Perspectives. Retrieved 2023-3-1
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