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Increased proinflammatory mediators leads to Recruitment of inflammatory cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis||adjacent||Moderate||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
|Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation||adjacent||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Frustrated phagocytosis leads to malignant mesothelioma||adjacent||High||Not Specified||Evgeniia Kazymova (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 Do not cite|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||Evgeniia Kazymova (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 Do not cite|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||Allie Always (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
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 Interleukin (IL)-1 family cytokines, IL-4, IL-5, IL-6, Tumor necrosis factor alpha (TNF-α), Interferon gamma (IFN-γ) (KE1496)
Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Hofman et al., 2016). With more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells (Villeneuve et al., 2018). Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.
Evidence Collection Strategy
Evidence Supporting this KER
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 and Sanz 2018).
Increased proinflammatory mediators means more proinflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villeneuve et al., 2018). Increased Signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophil (Khatri et al., 2017; Leick et al., 2014; Marchini et al., 2016). The leukocytes will differentiate into mature proinflammatory cells, in response to mediators they encounter in the local tissue microenvironment (Villeneuve et al., 2018). With higher levels of leukocytes from increased proinflammatory mediators, it causes an increase in proinflammatory cells (Libby, 2015).
Uncertainties and Inconsistencies
Attenuation or complete abrogation of KE1 (KE1496) and KE2 (KE1497) following inflammogenic stimuli is observed in rodents lacking functional IL-1R1 or other cell surface receptors that engage innate immune response upon stimulation (Gasse et al., 2007; Halappanavar et al., 2013). 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 MWCNTs was suppressed at 24 hr in mice deficient in IL-1R1 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 damage-associated molecular patterns 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
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
Air pollution primes immunity; increases the levels of circulating IL-1β, IL-6 and TNF-α; impairs the normal functions of macrophages and alveolar cells. Exposure to particulate air pollution, such as PM2.5, is associated with pulmonary inflammation (1,2). Both short term and chronic exposures to fine particulate matter (PM) have been shown to increase levels of circulating IL-1β, IL-6 and TNF-α (3-5). Air pollution works as a priming factor that exacerbates the inflammatory phenotype of COVID-19 and further dysregulates immune cell activity. Dysregulation of the immune cell functions, on the other hand, plays a role in tissue damage and the ability of the immune system to fight pathogens, which increases the susceptibility to concomitant bacterial superinfection, for instance (6-9).
1) Zhao et al., 2013
2) Jia et al., 2021
3) Tsai et al., 2012
4) Ljungman et al., 2009
5) Kido et al., 2011
6) Knoll et al., 2021
7) Glencross et al., 2020
8) Yamasaki and Eeden, 2018
9) Signorini et al., 2018
Chemicals (weak evidence)
Per- and polyfluoroalkyl substances (PFAS) (Perfluorooctane sulfonate [PFOS], perfluorooctanoic acid [PFOA], perfluorobutane sulfonic acid [PFBS], perfluorooctane sulfonamide [PFOSA], and perfluorodecanoic acid [PFDA])
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 . 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 ; both PFOS and PFOA enhanced IL-1β release in response to Poly I:C ; 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 . 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. Tian et al., 2021
2. Li et al., 2020
3. Sørli et al., 2020
4. Corsini et al., 2012
5. Han et al., 2018
6. EFSA CONTAM Panel, 2020
|sex||female sex (XX chromosomes)||
Females produce higher amounts of the antiviral infection cytokine IFN-α than men . 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 (Treg cells), 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 . In the presence of progesterone, CD4+ Th cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL-4 and IL-10 . 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 . In lactating women, higher SARS-CoV-2 reactive memory B-cells and antibody titers have been associated with the hormone prolactin . Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients.
1. Takahashi et al., 2020
2. Scully et al., 2020
3. Mauvais-Jarvis et al., 2020
4. Gonçalves et al., 2021
|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 . Moreover, elderly men in particular display autoantibodies against IFN-α more frequently . 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 . Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-α , IL-8 and IL-18 , driving hyperinflammation and more pronounced lymphopenia in males.
5. Bastard et al., 2020
6. Agrawal et al., 2021
|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 . 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 in response to infection with the influenza virus .||
1. Bonafè et al., 20202. Kovacs et al., 2017
Lipids impact innate and adaptive immune responses (1,2).
In COVID-19. The atherogenic dyslipidemia associated with COVID-19 severity (high tryglycerides and low total, low density lipoprotein and high density lipoprotein cholesterol) was inversely correlated with inflammatory biomarkers such as increased levels of serum C-reactive protein (CRP), IL-6, IL-8, and IL-10 [3,4].
1. Hubler and Kennedy, 2016
2. Bernardi et al., 2018
3. Henry et al., 2021
4. Caterino et al., 2021
5. Hubler and Kennedy, 2016
6. Winer et al., 2009
7. Im et al., 2011
8. Muscogiuri et al., 2020
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 . Th1 lymphocytes are more prevalent in adipose tissue of obese patients . In the same way, Th1 lymphocytes are elevated in visceral fat . Both macrophages and T lymphocytes interact with lipids that influence their proliferation, differentiation, polarization  and transcriptional regulation, which is tightly controlled by Sterol regulatory element-binding protein (SREBP) and Liver X receptors (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 .
|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 . SCFAs modulate inflammation by regulating immune cell cytokine production such as TNF-α, IL-12, IL-6 . For example, butyrate decreased the LPS-induced TNF-α expression in monocytes  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 gastrointestinal system) was linked to increased plasma concentrations of TNF-α, CXCL10, CCL2 and IL-10 . 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 , 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 . 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 .
1. Yoo et al., 2020
2. Vinolo et al., 2011
3. Atarashi et al., 2013
4. Yeo et al., 2021
5. Gou et al., 2021
6. Zuo et al., 2020
7.Gu et al., 2020
8. Grenga et al., 2022
9. Sencio et al., 2022
10. Zhang et al., 2022
|Vitamin D (low evidence)||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-α and downstream of Nuclear Factor Kappa B Subunit 1 (NF–κB1) signaling pathway, which regulates inflammatory reactions toward viral infection in macrophages [1,2]. Vitamin D was shown as a potent suppressor of IFN-γ mediated macrophages response, preventing the release of inflammatory cytokines and chemokines . Thus, release of pro-inflammatory cytokines might be exacerbated in COVID-19 patients with vitamin D deficiency .
 Hassan et al., 2022
 Książek et al., 2021
 Helming et al., 2005
 Munshi et al., 2021
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 . 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 multisystem inflammatory syndrome in Children (MIS-C) .
 Singh et al., 2020
 Rowley, 2020
|Therapeutic intervention against COVID-19.||Tocilizumab and Sarilumab||
Are anti-IL-6 receptor monoclonal antibodies, which reduce inflammation  by attaching to the
IL-6 receptor (as IL-6 receptor inhibitors) . Tocilizumab, a biological drug approved
for rheumatoid arthritis, is currently being evaluated for its efficacy against the effects of
systemic IL-6 elevation (ClinicalTrial.gov accessed on March 2022, NCT04317092,NCT04320615, NCT04306705) .
1) WHO, 2021.
2) European Medicines Agency, 2021
3) Bonafè et al., 2020
Is an immunosuppressant that blocks the action of enzymes known as Janus kinases (JK), which play an important role in inflammatory processes (JAK inhibitor) [1–4].
1) Jorgensen et al., 2020
2) Bekerman et al., 2017
3) Neveu et al., 2015
4) Richardson et al., 2020
|Low molecular weight heparins (LMWHs)||
Have anti-inflammatory effects by blocking pro-inflammatory mediators (TNF-α, IL-6 and Leukotriene [LTB4]) .
1) Buijsers et al., 2020
|Pre-existing heart failure||
Dysregulation of renin angiotensin system due to pre-existing HF can have detrimental inflammatory effects both locally (in the heart) and systematically.
The Angiotensin converting enzyme 2 (ACE2)/Angiotensin (Ang) (1-7) pathway is associated with the attenuation of a wide range of pro-inflammatory cytokines and chemokines,
such as IL-1, IL-5, IL-6, IL-12, CCL2, TNF-α and MCP-1 .
|1: Rodrigues Prestes et al., 2017.|
|Diet||Dietary elements linked to pro-inflammatorymediators||
Known Feedforward/Feedback loops influencing this KER
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
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