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Relationship: 924

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Cell injury/death leads to Release, Cytokine

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Cell injury/death

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Release, Cytokine

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	High	NCBI
human	Homo sapiens	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cell death, including both necrosis and apoptosis can lead toward inflammation. Faouzi and colleagues showed that apoptosis can induce hepatic inflammation equally as necrosis (Faouzi et al., 2001). Some studies indicate that phagocytes can produce inflammatory cytokines upon ingestion of apoptotic bodies (Uchimura et al., 1997).

When cells undergo necrosis they lose the integrity of their plasma membrane and release their intracellular contents, into the extracellular space. The same process can occur when apoptotic cells aren't cleared fast enough and their membrane becomes permeable to macromolecules, which presents secondary necrosis (Majno et al., 1995). There is evidence that the immune system has evolved the capacity to detect the release of intracellular molecules which stimulates the generation of adaptive immune responses to dying cells.

Intracellular content of dying cells that triggers immune response when excreted contains molecules named danger associated molecular patterns (DAMPs). DAMPs include for example HMGB-1, IL-1α, uric acid, DNA fragments, mitochondrial content, and ATP (Eigenbrod et al., 2008; Kono et al., 2010a; Sauter et al., 2000). DAMPs can be molecules that have non-inflammatory functions in living cells (such as HMGB-1, ATP) and acquire immunomodulatory properties when released (Rock and Kono, 2008), or alarmins, molecules that have cytokine-like properties (such as IL-1α, IL-6), which are stored in cells and released after cell lysis and contribute to the inflammatory response (Oppenheim and Yang, 2005; Vanden Berghe et al., 2006).

One of the most investigated DAMPs is HMGB-1 (Lotze et al., 2005). HMGB-1 is a nuclear protein that binds to chromatin and has a role in bending DNA and regulating gene transcription (Landsman et al., 1993). HMGB-1 is released by both necrotic and apoptotic cells (Scaffidi et al., 2002; Bell et al., 2006), but also apoptotic cells activate macrophages that engulf them to secrete HMGB-1 (Qin et al., 2006). This protein induces inflammation, dendritic cells maturation, migration, and T-cell activation (Scaffidi et al., 2002; Messmer et al., 2004; Rovere –Querini et al., 2004; Dumitriu et al., 2005; Yang et al., 2007).

HMGB-1 is a stimulus for tumour necrosis factor (TNF) synthesis and release, but it also significantly activates the synthesis of IL-1 α, IL-1 β, IL-1RA, IL-6, IL-8, MIP-1 a, and MIP-1 (Andersson et al., 2000). It was shown that HMGB-1 released from late apoptotic cells remains bound to nucleosomes and that HMGB1-nucleosome complexes activate antigen-presenting cells (APC) and induce secretion of cytokines by macrophages and expression of co-stimulatory molecules in DCs (Urbonaviciute et al., 2008).

HMGB-1 is not the only pro-inflammatory DAMP released from dying cells. Other DAMPs, S100A8/A9 and S100A12 proteins induce pro-inflammatory cytokine production by macrophages (Hofmann et al., 1999; Yang et al., 2001; Viemann et al., 2004; Ehlerman et al., 2006; Pouliot et al., 2008).

The adjuvant activity of cells was reduced by enzymatic depletion of uric acid, indicating that it is a major DAMP, at least in some cells (Shi et al., 2003). Uric acid is a mediator released from necrotic or apoptotic cells that has immunostimulatory properties in vivo (Gordon et al., 1985; Shi et al., 2003).

Insufficient autophagy of deteriorated mitochondria could lead to massive release of DAMPs such as mtDNA and possibly other mitochondrial proteins (Oka et al., 2012).

Receptors on host cells sense when DAMPs are released and that triggers the inflammatory process. These receptors are pattern-recognition receptors (PRRs) (Chen and Nunez, 2010). PRRs represent proteins by which cells recognize microbial entities, but also some of the host's own molecules and direct an immune response (Piccinini et al., 2010). PRRs can be broadly divided in five subfamilies: Toll-like receptors (TLRs), RIG-1-like receptors (RLRs), NOD like receptors (NLRs), AIM2-like receptors (ALRs) and C-type lectin receptors (CLRs) (Takeuchi and Akira, 2010; Wang et al., 2014). For example, HMGB-1 was reported to stimulate TLR2 and TLR4 (Park et al. 2004) and receptor for advanced glycation end products (RAGE) (Dumitriu et al., 2005), while NLRP3 has been involved in the inflammatory response to mono-sodium urate (MSU) (Martinon et al., 2006). Cellular nucleic acids can stimulate TLR7 and TLR9 on B cells to promote antibody responses (Green and Marshak-Rothstein, 2011; Leadbetter et al., 2002).

TLRs are placed either at the cell surface (TLR1, TLR2, TLR4, TLR5, and TLR6) or in the endolysosomal compartment (TLR3, TLR7, and TLR9) (Barton and Kagan, 2009). Upon binding with the ligand, they undergo a conformational change and initiate a signalling cascade via signal adaptor molecules: myeloid differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (MAL, also known as TIR-domain-containing adaptor protein; TIRAP), TIR domain-containing adaptor protein inducing interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM). MyD88 was essential for the inflammatory response to injected dead cells (Chen et al., 2007).

All TLRs, except TLR3, associate with MyD88, and this stimulates a kinase cascade resulting in the activation of mitogen activated protein kinases (MAPKs), c-Jun N-terminal kinases, p38, and extracellular signal–regulated kinases, and nuclear factor NF-kB (Akira and Takeda, 2004; Lee and Kim, 2007). NF-kB is an important transcription factor for IL -1β and NLRP3 (Wang et al., 2004; Bauernfeind et al., 2009).

NF-kB is a central mediator of pro-inflammatory gene induction and functions in both types of immune cells. NF-kB pathway is responsible for transcriptional induction of pro-inflammatory cytokines, chemokines and additional inflammatory mediators, such as NLRP3, pro-IL-1β and pro-IL-18 (Sun et al., 2013; Ghosh and Karin, 2002; Hayden and Ghosh, 2013).

Macrophages must first be ‘primed’ with a stimulus that induces the synthesis of pro-IL -1β and also upregulates the expression of NLRP3 (Bauernfeid et al., 2009; Franchi et al., 2009). The stimuli that can prime macrophages include TLR agonists and cytokines like TNF. When macrophages producing pro-IL -1β are stimulated with ATP or irritant particles, inactive pro-caspase 1 assembles into a molecular complex called the inflammasome and is cleaved into active form (Stutz et al., 2009; Schroder and Tschopp, 2010). Inflammasomes consist of caspase 1, apoptosis-associated speck-like protein containing CARD (ASC) and an NLRP (Schroder and Tschopp, 2010). The catalytically active caspase 1 then cleaves pro-IL-1β to its mature and active form (Stutz et al., 2009). Macrophages lacking any of the inflammasome components don't make mature IL-1 when stimulated in culture with sterile particles (Hornung et al., 2008; Halle et al., 2008). NF-κB signaling pathway is also involved in the regulation of inflammasome (Guo et al., 2015).

Sometimes substantial sterile inflammatory response can be seen in caspase 1-deficient mice (eg. Chen et al., 2007). This contrasts with the much more marked reduction of these responses that is consistently observed in IL-1β -deficient mice. These data imply that there must be a caspase 1-independent pathway for generating mature IL-1β in vivo (Dinarello, 2009).

In the sterile inflammatory response to cell death, the contribution of TNF appears to be more modest than IL-1 (Rock et al., 2011). A possible explanation might be that the IL-1 is being released from the dying cells themselves (Eigenbrod et al., 2008).

After engulfment of apoptotic bodies, Kupffer cells in liver express TNF, TNF-related apoptosis-inducing ligand (TRAIL), and Fas ligand (FasL) (Canbay et al. 2003), which can induce apoptosis in hepatocytes and further aggravate liver inflammation. Engulfment of apoptotic bodies by macrophages also induces FasL expression (Kiener et al., 1997), which is known to exert a pro-inflammatory activity (Chen et al., 1998).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The severity of cell death activation determines the outcome for the cell: inflammation is part of the tissue regeneration process, and intermediate apoptotic stimuli are able to trigger this response. Recruitment of inflammatory cells such as neutrophils is meant as a beneficial process, as for example apoptotic bodies of bacteria-infected cells can be removed. Thus the apoptotic cells can secrete soluble "find-me" factors that trigger infiltration of immune cells. However, if this becomes chronic it has the potential to enhance tissue damage and ultimately induce fibrosis (Jaeschke, 2002; Cullen et al., 2013).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

During the apoptosis of Jurkat cells treated with various agents, HMGB-1 was released into the media as assessed by Western blotting. This release was blocked by an inhibitor of apoptosis (Bell et al., 2006).

Some studies reported that purified HMGB-1 activate leukocytes and stimulate the production of pro-inflammatory mediators in vitro (Li et al., 2004; Zimmermann et al., 2004).

Injecting a neutralizing HMGB-1 antibody into animals treated with a hepatotoxic drug, reduced inflammation in the damaged liver (Scaffidi et al., 2002). Other studies showed that anti-HMGB-1 antibodies could also reduce inflammation in livers that had suffered from ischemia-reperfusion injury (Tsung et al., 2005).

In uric acid-depleted mice, the inflammatory responses to cell death were significantly reduced (Kono et al., 2010a).

ATP can stimulate the production of pro-inflammatory cytokines from macrophages (Ferrari et al., 1997; Ferrari et al., 2006). Depletion of ATP or elimination of its receptor inhibited inflammation in vivo in reaction to thermal injury of the liver (McDonald et al., 2010).

Injection of an agonistic anti-FAS antibody into mice causes hepatocytes to undergo apoptosis which stimulates inflammation. If apoptosis is blocked, then this inflammatory response is inhibited (Faouzi et al., 2001).

Chen and colleagues injected dead cells into mice that genetically lacked various TLR. Inflammation was reduced in mice that were doubly-deficient in TLR2 and TLR4, confirming that these receptors play a role in the sterile inflammatory response. However reduction in the response was mild, indicating that there must be other receptors involved in this process (Chen et al., 2007).

IL-1 receptor antagonist (IL-1RA) administration resulted in a significant decrease in IL-6, and a borderline decrease in TNF production. This antagonist does not reduce the number of apoptotic bodies present, indicating that its effect on IL-6 and TNF- levels were due to neutralization of IL-1 (Clarke et al., 2010). Knock out of IL-1 receptor antagonist results in lethal artery inflammation (Nicklin et al., 2000).

The IL-1-dependent inflammatory response to cell death in vivo is significantly reduced in NLRP3-deficient mice (Imaeda et al., 2009; Iyer et al., 2009).

Death-induced neutrophilic inflammation was markedly decreased in mice lacking MyD88. However, this effect was primarily due to a key role for the IL-1 receptor in the recruitment of neutrophils (Chen et al., 2007).

Neutralization of IL-1α or genetic deficiency of IL-1 inhibited inflammation responses to injected dead cells (Kono et al., 2010b; Chen et al., 2007).

Injection into mice of a variety of other dead cell types that genetically lack both IL-1α and IL- 1β stimulated an inflammatory response that was equivalent to that of wildtype necrotic cells (Kono et al., 2010b). This implicates that IL-1 that is driving the sterile inflammatory response in many cases is not coming directly from the dead cell but is produced by cells in the host upon recognition of cell death. That this is the case was formally shown by the loss of inflammatory response to dead cells in mice that genetically lack either IL-1α or IL-1β (Kono et al., 2010b).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

No dose-response or time dependency is described; proof is presented mainly by using respective inhibitors.

The inflammatory role of HMGB-1 is still not completely clear. There are many studies that confirm its pro-inflammatory activity. However, in some experiments highly purified HMGB-1 had little pro-inflammatory activity (Rouhiainen et al., 2007), while in another injection of recombinant HMGB-1 into infarcted heart muscle in vivo stimulated regeneration and repair (Limana et al., 2005).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Human (Andersson et al., 2000; Scaffidi et al., 2002; Bell et al., 2006; Clarke et al., 2010)

Mouse (Faouzi et al., 2001; Chen et al., 2007)

References

List of the literature that was cited for this KER description. More help

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