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Relationship: 1703


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

Increased proinflammatory mediators leads to Recruitment of inflammatory cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Substance interaction with the lung resident cell membrane components leading to lung fibrosis adjacent Moderate Low Sabina Halappanavar (send email) Under development: Not open for comment. Do not cite EAGMST Under Review
Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation adjacent Penny Nymark (send email) Under development: Not open for comment. Do not cite Under Development
Frustrated phagocytosis leads to malignant mesothelioma adjacent High Not Specified Penny Nymark (send email) Under development: Not open for comment. Do not cite
Interaction with lung resident cell membrane components leads to lung cancer adjacent Moderate Low Penny Nymark (send email) Under development: Not open for comment. Do not cite
Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death) adjacent High High Laure-Alix Clerbaux (send email) Under development: Not open for comment. Do not cite

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

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

Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. They are secreted following inflammation or exposure to an inflammogen. Commonly measured pro-inflammatory mediators include IL-1 family cytokines, IL-4, IL-5, IL-6, TNFa, IFNg (KE1496)

 Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Koller, more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells (Villenueve et al, Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.

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 biological plausibility of this KER is high. There are very well established functional relationships between the secreted signalling molecules and the chemotactic effects on pro-inflammatory cells (Harris, 1954; Petri & Sanz 2018).

Increased proinflammatory mediators means more proinflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villenueve et al, Increased Signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophil (Leick et al, doi: 10.1007/s00441-014-1809-9). The leukocytes will differentiate into mature proinflammatory cells, in response to mediators they encounter in the local tissue microenvironment (Villenueve et al, With higher levels of leukocytes from increased proinflammatory mediators, it causes an increase in proinflammatory cells (Libby,

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

Attenuation or complete abrogation of KE1 (KE1496) and KE2 (KE1497) ollowing inflammogenic stimuli is observed in rodents lacking functional IL-1R1 or other cell surface receptors that engage innate immune response upon stimulation. However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNT was suppressed at 24 hr in mice deficient in IL1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving DAMPs is fundamental for survival, which may necessitate activation of compensatory signalling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response.

Most of the studies evaluate one dose at different time points or one-time point at different concentrations. Moreover, some studies have demonstrated that a stressor can lead to the recruitment of pro-inflammatory cells, but the presence of pro-inflammatory mediators was not determined (Westphal et al., 2015).

Recruitment of pro-inflammatory cells is a key event that is complicated to replicate in vitro conditions as cell migration is induced by cooperative chemotactic mediators (Gouwy et al., 2015) which are produced and released from different cells. Therefore, more kinetics studies in co-culture techniques are needed to fill this gap.

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)

Chemicals (weak evidence)


Several in vitro studies in human-derived cells have shown that PFAS can modify the secretion of pro-inflammatory mediators in a dose-dependent manner [1].  PFOS exposure significantly induced IL-1 IL-4, IL-6, and IL-8 in human lymphocytes and reduced chemokines CXCL8 and CXCL10 secretion in human bronchial epithelial cells while increasing of IL-1α release [2]; both PFOS and PFOA enhanced IL-1β release in response to Poly I:C [3]; PFOS, PFOA, PFBS, PFOSA, and PFDA exposure decreased PHA-induced release of IL-4, IL-10, and IL-6 and PFOS, PFOSA, and PFDA decreased IFN-γ release in human leukocytes with PFOS as a more potent inhibitor of cytokine production than other PFAS, and leukocytes obtained from female donors appeared to be more sensitive to the in vitro immunomodulating effects of PFAS, compared to leukocytes from male donors [4]. In a rat study exposed to PFOS, increased serum levels of TNF-α and IL-6 were observed. Kupffer cells exposed to PFOS showed cell activation, which was mostly inhibited by anti-TNF-α or anti-IL-6 treatment. Moreover, NF-κB inhibitor and JNK inhibitor significantly inhibited the production of IL-6 [5,6].

1. doi:10.1016/j.ecoenv.2021.112128

2. doi: 10.1016/j.chemosphere.2020.127062

3. doi: 10.1016/j.tiv.2019.104656

4. doi: 10.1016/j.taap.2011.11.004

5. doi: 10.1016/j.chemosphere.2017.08.070

6. doi:10.2903/j.efsa.2020.6223

sex female sex (XX chromosomes)

Females produce higher amounts of the antiviral infection cytokine IFN- a than men [1].  Estrogens are critical regulators of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as lymphocytes such as T-helper 1/2 (TH1/2) cells, regulatory T-cells (Tregs), and B cells. One of the major forms of estrogen, estradiol, has been shown to dampen the production of excessive innate inflammatory cytokines by monocytes and macrophages [2]. In the presence of progesterone, CD4+ T-helper cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL-4 and IL-10 [3]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct and immune response in females is enriched with activated T-cells [1]. In lactating women, higher SARS-CoV-2 reactive memory B-cells and antibody titers have been associated with the hormone prolactin [4]. Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients.

1. doi: 10.1038/s41586-020-2700-3

2. doi: 10.1038/s41577-020-0348-8

3. doi: 10.1016/S0140-6736(20)31561-0

4. doi: 10.1016/j.xcrm.2021.100468

male sex (XY chromosomes)

Males display a higher innate immune response to SARS-CoV-2 than females,which conditions their cytokine profile. Men have higher levels of the innate immune cytokines IL-8 and IL-18 in circulation  [1]. Moreover, elderly men in particular display autoantibodies against IFN-a more frequently [5]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct. Men display higher circulating levels of non-classical monocytes [1]. Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-a [6], IL-8 and IL-18 [1], driving hyperinflammation and more pronounced lymphopenia in males.


5. doi: 10.1126/science.abd4585

6. doi: 10.3389/fimmu.2021.739757


Old people During aging, a subclinical chronic inflammatory response develops leading to an immune senescent state, where pathogen protective immune responses are impaired, but the production of inflammatory cytokines, such as IL-6, is increased. This process is called inflammaging. The persistent IL-6 elevation can induce lung tissue inflammation and mortality. The rate of inflammaging is higher in men and accelerated inflammaging is believed to worsen COVID-19 outcomes [1]. The chronic inflammatory status is associated with a dramatic depletion of B lymphocyte-driven acquired immunity. Aging also attenuates the upregulation of co-stimulatory molecules critical for T-cell priming and reduces antiviral IFN production by alveolar macrophages and dendritic cells (DCs) in response to infection with the influenza virus [2].

1. doi: 10.1016/j.cytogfr.2020.04.005

2. doi. 10.1016/j.cger.2017.06.002

Atherogenic dyslipidemia

Lipids impact innate and adaptive immune responses (1,2).

In COVID-19. The atherogenic dyslipidemia associated with COVID-19 severity (high TG and low total, LDL and HDL cholesterol) was inversely correlated with inflammatory biomarkers such as increased levels of serum CRP, IL-6, IL-8, and IL-10 [3,4].

1. doi: 10.1016/j.jnutbio.2015.11.002

2. doi: 10.3390/ijms19124058

3. doi: 10.1016/j.dsx.2021.04.011

4. doi: 10.1038/s41598-021-82426-7

5. doi: 10.1016/j.jnutbio.2015.11.002

6. doi: 10.1038/nm.2001

7. doi: 10.1016/j.cmet.2011.04.001

8. doi: 10.1016/j.metabol.2020.154251


In obesity, immune cells interact with various classes of lipids, which can control the plasticity of macrophages and T lymphocytes.

In COVID-19. Altered lipid homeostasis is associated with severe COVID-19 outcomes and, at the same time, with chronic inflammation and inflammatory polarization of macrophages and T lymphocytes [5]. Th1 lymphocytes are more prevalent in adipose tissue of obese patients [6]. In the same way, Th1 lymphocytes are elevated in visceral fat [6]. Both macrophages and T lymphocytes interact with lipids that influence their proliferation, differentiation, polarization [7] and transcriptional regulation, which is tightly controlled by SREBP and LXRs, expressed in macrophages and known regulators of cytokine release. Adipose tissue produces many pro-inflammatory adipokines and cytokines, which lead to low-grade inflammation and the recruitment of immune cells which may clarify the connection between obesity and COVID-19 severity [8].

Gut microbiota Gut dysbiosis (alteration of gut microbiota)

The gut microbiota is increasingly acknowledged to play a central role in human health and disease, notably by shaping the immune response. Notably some bacteria living in the gut produce short-chain fatty acids (SCFA), recognized as mediators of the intestinal inflammatory response [1]. SCFAs modulate inflammation by regulating immune cell cytokine production such  as TNF-α, IL-12, IL-6 [2]. For example, butyrate decreased the LPS-induced TNFα expression in monocytes [4] and activated Treg cells, blocking an excessive inflammatory response [1,3].

In COVID-19. In a COVID-19 cohort, the depletion of several bacterial species (B. adolescentis, E. rectale and F. prausnitzii, known to play immunomodulatory roles in the human GI system) was linked to increased plasma concentrations of TNF-α, CXCL10, CCL2 and IL-10 [4]. Conversely, two species enriched in the COVID-19 cohort, B. dorei and Akkermansia muciniphila, were positively correlated with IL-1β, IL-6 and CXCL8. Using a machine learning model [5], it was reported that the disruption of gut microbiota significantly correlated with pro-inflammatory cytokines and may predispose normal individuals to severe COVID-19. Decreases in the abundance of butyrate-producing bacteria and a decline in SCFA were observed in severe COVID-19 [4,6,7,8]. Reduced relative proportion of bacteria producing SCFA was observed in Syrian hamsters infected with SARS-CoV-2, compared to non-infected controls, with a transient decrease in systemic SCFA amounts [9]. However, SCFA supplementation in hamsters during infection had no effect on inflammatory parameters. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs in COVID-19 patients, which correlated with disease severity and increased plasma concentrations of CXCL-10 and CRP [10].

1. doi: 10.3390/microorganisms8101587

2. doi: 10.3390/nu3100858

3. doi: 10.1038/nature12331

4. doi: 10.1136/gutjnl-2020-323020

5. doi: 10.1016/j.jgg.2021.04.002

6. doi: 10.1053/j.gastro.2020.05.048

7.doi: 10.1093/cod/ciaa709

8. doi: 10.21203/

9.doi: 10.1080/19490976.2021.2018900

10. doi: 10.1053/j.gastro.2021.10.013

Vitamin D Vitamin D deficiency

There is a complex interplay between vitamin D and the immune response to viral infections. Low vitamin D status is proposed to induce upregulation of the TNF-_ and downstream of NF–kB1 signaling pathway, which regulates inflammatory reactions toward viral infection in macrophages [1,2]. Vitamin D was shown as a potent suppressor of IFN--mediated macrophages response, preventing the release of inflammatory cytokines and chemokines [3]. Thus, release of pro-inflammatory cytokines  might be exacerbated in COVID-19 patients with vitamin D deficiency [4].

[1] doi: 10.1007/s10528-021-10116-0

[2] doi:10.3390/ijerph18137124

[3] doi: 10.1182/blood-2005-03-1029

[4] doi: 10.1002/jmv.26360

genetic factors  

The inflammatory response manifested by increased cytokine levels results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. In the 50-non-coding regions of the HO-1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T (-413) A sites, which regulate the transcriptional activity of HO-1. These polymorphisms have been shown to be associated with the occurrence and progression of numerous diseases, including COVID-19 [1]. The timing of the IFN response to SARS-CoV-2 infection can vary with viral load and genetic differences in host response. When the viral load is low, IFN responses are engaged and contribute to viral clearance, resulting in mild infection. When viral load is high and/or genetic factors slow antiviral responses, virus replication can delay the IFN response and cytokine storm can occur before adaptive responses clear the virus, resulting in severe disease including MIS-C [2].

[1] doi: 10.1016/j.freeradbiomed.2020.10.016

[2] doi: 10.1038/s41577-020-0367-5

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

Activated pro-inflammatory cells secrete pro-inflammatory mediators, and those mediators' goal is to cause signalling and response, which can lead to chronic inflammation (KE1497). Chronic inflammation means proinflammatory mediators increase and increased recruitment of inflammatory cells acts in a positive feedback loop, which continues a pro-inflammatory environment.

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


List of the literature that was cited for this KER description. More help
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  8. Gouwy, M et al. Serum amyloid A chemoattracts immature dendritic cells and indirectly provokes monocyte chemotaxis by induction of cooperating CC and CXC chemokines. Eur. J. Immunol. 2015. 45:101-112.
  9. Hadrup N et al. Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology, 2019, 13(9): 1275-1292.
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