Damage-associated molecular pattern

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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 (PRR). [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 (PAMPs) 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]

Contents

Overview

DAMPs and their receptors are characterized as: [3]

Table 1. List of DAMPs, their origins, and their receptors
OriginMajor DAMPsReceptors
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]

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
CategoryDAMPMolecular structure or epitopeSource or precursorReceptor or signaling regulatorSpecies
Epidermis cuticleCutin monomersC16 and C18 hydroxy and epoxy fatty acidsEpidermis cuticleUnknownArabidopsis thaliana, Solanum lycopersicum
Cell wall polysaccharide fragments or degrading productsOGsPolymers of 10–15 α-1-4-linked GalAsCell wall pectinWAK1 (A. thaliana)A. thaliana, G. max, N. tabacum
CellooligomersPolymers of 2–7 β-1,4-linked glucosesCell wall celluloseUnknownA. thaliana
Xyloglucan oligosaccharidesPolymers of β-1,4-linked glucose with xylose, galactose, and fructose side chainsCell-wall hemicelluloseUnknownA. thaliana, Vitis vinifera
MethanolMethanolCell wall pectinUnknownA. thaliana, Nicotiana tabacum
Apoplastic peptides and proteinsCAPE111-aa peptideApoplastic PR1UnknownA. thaliana, S. lycopersicum
GmSUBPEP12-aa peptideApoplastic subtilaseUnknownGlycine max
GRIp11-aa peptideCytosolic GRIPRK5A. thaliana
Systemin18-aa peptide (S. lycopersicum)Cytosolic prosysteminSYR1/2 (S. lycopersicum)Some Solanaceae species
HypSys15-, 18-, or 20-aa peptidesApoplastic or cytoplasmic preproHypSysUnknownSome Solanaceae species
Peps23~36-aa peptides (A. thaliana)Cytosolic and vacuolar PROPEPsPEPR1/2 (A. thaliana)A. thaliana, Zea mays, S. lycopersicum, Oryza sativa
PIP1/211-aa peptidesApoplastic preproPIP1/2RLK7A. thaliana
GmPep914/8908-aa peptideApoplastic or cytoplasmic GmproPep914/890UnknownG. max
Zip117-aa peptideApoplastic PROZIP1UnknownZ. mays
IDL6p11-aa peptideApoplastic or cytoplasmic IDL6 precursorsHEA/HSL2A. thaliana
RALFs~50-aa cysteine-rich peptidesApoplastic or cytoplasmic RALF precursorsFER (A. thaliana)A. thaliana, N. tabacum, S. lycopersicum
PSKs5-aa peptidesApoplastic or cytoplasmic PSK precursorsPSKR1/2 (A. thaliana)A. thaliana, S. lycopersicum
HMGB3HMGB3 proteinCytosolic and nuclear HMGB3UnknownA. thaliana
Inceptin11-aa peptideChloroplastic ATP synthase γ-subunitUnknownVigna unguiculata
Extracellular nucleotideseATPATPCytosolic ATPDORN1/P2K1 (A. thaliana)A. thaliana, N. tabacum
eNAD(P)NAD(P)Cytosolic NAD(P)LecRK-I.8A. thaliana
eDNADNA fragments < 700 bp in lengthCytosolic and nuclear DNAUnknownPhaseolus vulgaris, P. lunatus, Pisum sativum, Z. mays
Extracellular sugarsExtracellular sugarsSucrose, glucose, fructose, maltoseCytosolic sugarsRGS1 (A. thaliana)A. thaliana, N. tabacum, Solanum tuberosum
Extracellular amino acids and glutathioneProteinogenic amino acidsGlutamate, cysteine, histidine, aspartic acidCytosolic amino acidsGLR3.3/3.6 or others (A. thaliana)A. thaliana, S. lycopersicum, Oryza sativa
GlutathioneGlutathioneCytosolic glutathioneGLR3.3/3.6 (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:

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]

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Toll-like receptor</span> Class of immune system proteins

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. This allows the innate immune system to recognize pathogens and thus, protect the host from infection.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">S100 protein</span> Family of vertebrate proteins involved in cell division and inflammation

The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are encoded by a family of genes whose symbols use the S100 prefix, for example, S100A1, S100A2, S100A3. They are also considered as damage-associated molecular pattern molecules (DAMPs), and knockdown of aryl hydrocarbon receptor downregulates the expression of S100 proteins in THP-1 cells.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">Toll-like receptor 6</span> Protein found in humans

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to a pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein found in humans

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.

<span class="mw-page-title-main">HMGB1</span> Mammalian protein found in Homo sapiens

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

Seung-Yong Seong is a South Korean immunologist and microbiologist known for his study of innate immune system response and his development of the damage-associated molecular pattern (DAMP) model of immune response initiation in collaboration with Polly Matzinger. Seong is also known for his research on the bacterium Orientia tsutsugamushi and his research on immunological adjuvant when he was a student. Since 2013 he has served as Director of the Wide River Institute of Immunology – Seoul National University in conjunction with his Professor position in the Microbiology and Immunology department of Seoul National University College of Medicine. In 2012, he became Editor in Chief of the World Journal of Immunology.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

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