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Relationship: 2834

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

Tissue resident cell activation leads to Increase, Pro-Inflammatory Mediators

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
Deposition of Energy Leading to Learning and Memory Impairment adjacent Moderate Low Vinita Chauhan (send email) Open for citation & comment

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
human Homo sapiens Low NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

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

Tissue-resident cell activation refers to the stimulation of resident cells in organ systems. Tissue-resident immune cells can be found throughout the body, each tissue and organ containing specific resident immune cells (Chen et al., 2018; Gray & Farber, 2022). Monocytes, found in the blood, and macrophages, found in all tissues in the body, are the main components of the immune system (Ivanova & Orekhov, 2016). In the brain, the primary tissue-resident macrophages are microglia, while astrocytes are also important cells found in the brain (Bourgognon & Cavanagh, 2020; Greene-Schloesser et al., 2012; Wang et al., 2020). Activated tissue-resident cells can undergo gliosis, whereby they adopt a hypertrophic morphology and proliferate, exhibiting rounding of the cell body and retraction of cell processes (Greene-Schloesser et al., 2012; Phatnani & Maniatis, 2015). It is well-characterized that activated tissue-resident cells can increase expression of pro-inflammatory mediators (Hladik & Tapio, 2016; Lumniczky, Szatmari & Safrany, 2017; Kaur et al., 2019). Acute inflammation from controlled biosynthesis of pro-inflammatory mediators protects tissue and promotes healing (Kim & Joh, 2006; Vezzani & Viviani, 2015). Prolonged tissue-resident cell activation leads to dysregulation in production or secretion of pro-inflammatory mediators, which results in chronic inflammation and damage to tissue (Kim & Joh, 2006; Vezzani & Viviani, 2015). Additionally, activated tissue-resident cells can show increased levels of transcription factor nuclear factor κB (NF-κB) and activated protein 1 (AP-1) DNA binding due to increased oxidative stress or DNA damage (Betlazar et al., 2016; Lumniczky, Szatmari & Safrany, 2017). Through the activity of NF-κB, AP-1 and other signaling pathways, activated immune cells can together produce/secrete a variety of cytokines and chemokines (Betlazar et al., 2016; Chen et al., 2018; Greene-Schloesser et al., 2012; Kim & Joh, 2006; Phatnani & Maniatis, 2015; Smith et al., 2012; Wang et al., 2020). Chronic secretion of these inflammatory proteins can lead to downstream detriments, such as in the brain, altering blood-brain barrier permeability (Lumniczky, Szatmari & Safrany, 2017). 

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

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

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

Overall Weight of Evidence: Moderate 

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

Tissue-resident cells recognize pathogens or molecules released by injured or activated cells (Vezzani & Viviani, 2015). In response, resident cells become activated and release various pro-inflammatory mediators (Chen et al., 2018; Gray & Farber, 2022). There is an abundance of studies which explore this relationship using the brain microenvironment, where astrocytes and microglia are the primary tissue-resident cells. After activation, these cells increase in number (whether through proliferation or recruitment), undergo morphological changes and release cytokines (Greene-Schloesser et al., 2012; Kim & Joh, 2006). 

Several pathways and molecules are involved in the inflammatory response to activate tissue-resident cells. These molecules include certain pro-inflammatory cytokines and various inflammatory stimuli, such as lipopolysaccharide (LPS), thrombin (a protease), β-amyloid (Aβ), interferon (IFN)-γ, CD40 and gangliosides (Dheen, Kaur & Ling, 2007; Kim & Joh, 2006). For example, LPS can diffuse into brain parenchyma and activate microglia, which then expresses inflammatory mediators and ROS to initiate inflammation (Dheen, Kaur & Ling, 2007; Kim & Joh, 2006). As well, pattern recognition receptor activation, through molecules such as damage-associated molecular pattern molecules (DAMPs), can activate tissue-resident cells and, in turn, lead to pro-inflammatory mediator secretion (Chen et al., 2018). 

Once resident cells become activated, various pathways, including the NF-κB transcription factor pathway and the mitogen-activated protein kinase (MAPK)-AP-1 signaling pathway, can result in pro-inflammatory mediator production (Chen et al., 2018; Vezzani & Viviani, 2015; Wang et al., 2020). When activated, microglia and astrocytes are sources of cytokines in the central nervous system (CNS) (Bourgognon & Cavanagh, 2020; Kim & Joh, 2006; Smith et al., 2012; Vezzani & Viviani, 2015; Boyd et al., 2021). Furthermore, uniquely in the brain, astrocyte activation can lead to blood-brain barrier permeability through decreased astrocyte function, which can allow pro-inflammatory mediators to enter from the blood (Lumniczky, Szatmari & Safrany, 2017). 

An abundance of studies supports the connectivity of the two key events using activated glial cells in the brain microenvironment. Activated astrocytes express high levels of glial fibrillary acidic protein (GFAP) (Greene-Schloesser et al., 2012), while microglia activation results in the expression of OX-42, Iba1 (activated and non-activated), Mac-1, CD68, F4-80, Glut-5 and CR3/43. These markers play an important role in the phagocytic activity and morphological changes of activated microglia (Jurga, Paleczna & Kuter, 2020). Upon expression of these markers, cells release pro-inflammatory mediators, these can further activate other glial cells (Bourgognon & Cavanagh, 2020). This results in an inflammatory state, that initiates the further release of cytokines including IL-1 and TNF-⍺, IL-6, Cox-2 (Betlazar et al., 2016; Kim & Joh, 2006; Smith et al., 2012) and chemokines MCP-1 and ICAM-1 (Greene-Schloesser et al., 2012; Kyrkanides et al., 2002). Chronic activation of these cells can result in neurodegenerative disease due to their continuous release and the overexpression of potentially cytotoxic molecules, which may eventually lead to cognitive decline (Dheen, Kaur & Ling, 2007; Kaur et al., 2019; Smith et al., 2012). To suppress this activity, anti-inflammatory proteins need to be released such as tumor growth factor (TGF)-β and IL-10; these act to reduce neuron activity (Kim & Joh, 2006; Phatnani & Maniatis, 2015). In a state of chronic inflammation, the production of pro-inflammatory proteins increases, while anti-inflammatory proteins decrease, and this imbalance results in a reduced stress response (Jeon & Kim, 2016). 

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
  • More work is needed to observe this relationship in human models

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  

Details  

Effects on the KER  

References  

Drug 

Flavonoids 

Flavonoids can inhibit NF-κB, preventing transcription of pro-inflammatory mediators in active glial cells. 

Wang et al., 2020 

Drug 

Tamoxifen (estrogen receptor 

modulator commonly used in breast cancer treatment) 

Treatment with Tamoxifen decreased the radiation-induced activation of glial cells. It also consistently decreased the amount of TNF-α and IL-1β and blood-brain barrier permeability after irradiation at various doses. 

Liu et al., 2010 

Drug 

RA (modulates inflammatory effects in different cell types) 

RA treatment completely inhibited the increase in pro-inflammatory mediators after LPS-induced glial activation. 

van Neerven et al., 2010 

Drug 

SP (JNK, c-jun N-terminal kinase, inhibitor) 

AP-1 DNA binding (glial activation) was reduced by SP treatment after irradiation. TNF-α, Cox-2 and IL-1β were reduced by SP treatment after irradiation or viral infection. 

Ramanan et al., 2008  

Drug 

Q (NF-κB inhibitor) 

NF-κB DNA binding (glial activation) was reduced by Q treatment after irradiation. IL-1β was also reduced by Q treatment after irradiation. 

Ramanan et al., 2008 

Drug 

NS-398 (Cox-2 inhibitor) 

Treatment with NS-398 reduced TNF-α, IL-1β, IL-6, ICAM-1 and MCP-1 expression after irradiation. 

Kyrkanides et al., 2002 

Age 

Increased age 

Aging tissue becomes more sensitive to immune signals and increases inflammation. In the aging brain, microglia will produce more pro-inflammatory mediators. 

Patterson, 2015 

Drug 

NAC 

NAC treatment inhibited pro-inflammatory mediator production in macrophages. 

Komatsu et al., 2017 

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

It is well-characterized that activated tissue-resident cells can increase expression of pro-inflammatory mediators (Hladik & Tapio, 2016; Lumniczky, Szatmari & Safrany, 2017; Kaur et al., 2019). However, there exists a feedforward loop for this key event relationship as pro-inflammatory mediators can also activate tissue-resident cells within the brain and perpetuate the inflammatory response (Kim & Joh, 2006; Vezzani & Viviani, 2015). Thus, after stimulation by cytokines, chemokines or inflammogens such as from damaged neurons, microglia and astrocytes activate inflammatory signaling pathways, which result in increased expression and/or release of inflammatory mediators such as cytokines, eicosanoids, and metalloproteinases (Dong & Benveniste, 2001; Bourgognon & Cavanagh, 2020). Various studies have shown that overexpression of IL-1β in moues models resulted in the appearance of inflammatory markers including activated glial cells and increased pro-inflammatory cytokine and chemokine mRNAs (Hein et al., 2010; Moore et al., 2009). Additionally, IL-6 plays a role in activating glial cells as mouse models with IL-6 knocked out showed reduced astrocytic population, as well as a reduced ability in activating microglia (Klein et al., 1997). Cytokines and chemokines can also increase the permeability of the blood-brain barrier, further increasing pro-inflammatory mediator levels (Lumniczky, Szatmari & Safrany, 2017). 

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

Evidence for this relationship comes from in vitro mouse- and human-derived models, as well as in vivo mouse and rat models. The relationship is not sex or life stage specific. 

References

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

Betlazar, C. et al. (2016), "The impact of high and low dose ionising radiation on the central nervous system", Redox Biology, Vol. 9, Elsevier B.V., https://doi.org/10.1016/j.redox.2016.08.002. 

Bourgognon, J. M. and J. Cavanagh. (2020), "The role of cytokines in modulating learning and memory and brain plasticity", Brain and Neuroscience Advances, Vol. 4, SAGE Publications, https://doi.org/10.1177/2398212820979802. 

Boyd, A. et al. (2021), "Control of Neuroinflammation through Radiation-Induced Microglial Changes", Cells, Vol. 10/9, Multi-Disciplinary Digital Publishing Institute (MDPI), Basel,  https://doi.org/10.3390/cells10092381. 

Chen, H. et al. (2016), "Delayed activation of human microglial cells by high dose ionizing radiation", Brain Research, Vol. 1646, Elsevier B.V., https://doi.org/10.1016/j.brainres.2016.06.002

Chen, L. et al. (2018). “Inflammatory responses and inflammation-associated diseases in organs”, Oncotarget, Vol.9/6, Oncotarger, Orchard Park, https://doi.org/10.18632/oncotarget.23208 

Dheen, S. T., C. Kaur and E. Ling. (2007), "Microglial Activation and its Implications in the Brain Diseases", Current Medicinal Chemistry, Vol. 14/11, Bentham Science Publishers https://doi.org/10.2174/092986707780597961. 

Dong, Y. and E. N. Benveniste. (2001), "Immune function of astrocytes", Glia, Vol. 36/2, John Wiley & Sons, Hoboken, https://doi.org/10.1002/glia.1107. 

Dong, X. et al. (2015), "Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice", International Journal of Radiation Biology, Vol. 91/3, Informa Healthcare, London, https://doi.org/10.3109/09553002.2014.988895. 

Gray, J. I., & D. L. Farber (2022). “Tissue-Resident Immune Cells in Humans”, Annual Review of Immunology, Vol. 40/1, Annual Reviews, San Mateo, https://doi.org/10.1146/annurev-immunol-093019-112809 

Greene-Schloesser, D. et al. (2012), "Radiation-induced brain injury: A review", Frontiers in Oncology, Frontiers Media, Lausanne, https://doi.org/10.3389/fonc.2012.00073. 

Hein, A. M. et al. (2010), "Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice", Brain, Behavior, and Immunity, Vol. 24/2, https://doi.org/10.1016/j.bbi.2009.10.002. 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research, Vol. 770, Elsevier B.V., https://doi.org/10.1016/j.mrrev.2016.08.003. 

Ivanova, E. A., & A. N. Orekhov. (2016), “Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy”, Journal of Immunology Research, Vol. 2016, Hindawi, https://doi.org/10.1155/2016/4789279 

Jeon, S. W. and Y. K. Kim. (2016), "Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?", World Journal of Psychiatry, Vol. 6/3, https://doi.org/10.5498/wjp.v6.i3.283. 

Jurga, A. M., M. Paleczna and K. Z. Kuter et al. (2020), "Overview of General and Discriminating Markers of Differential Microglia Phenotypes", Frontiers in Cellular Neuroscience, Vol. 14, Frontiers Media S.A., Lausanne, https://doi.org/10.3389/fncel.2020.00198

Kaur, D., V. Sharma and R. Deshmukh. (2019), "Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease", Inflammopharmacology, Vol. 27/4, Springer Nature, Berlin, https://doi.org/10.1007/s10787-019-00580-x. 

Kim, Y. S. and T. H. Joh. (2006), "Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease", Experimental & Molecular Medicine, Vol. 38/4, Springer Nature, Seoul, https://doi.org/10.1038/emm.2006.40

Klein, M. A. et al. (1997), "Impaired neuroglial activation in interleukin-6 deficient mice", Glia, Vol. 19/3, https://doi.org/10.1002/(SICI)1098-1136(199703)19:3<227::AID-GLIA5>3.0.CO;2-W. 

Komatsu, W. et al. (2017), “Nasunin inhibits the lipopolysaccharide-induced pro-inflammatory mediator production in RAW264 mouse macrophages by suppressing ROS-mediated activation of PI3 K/Akt/NF-κB and p38 signaling pathways”, Bioscience, Biotechnology, and Biochemistry, Vol. 81/10, Elsevier, https://doi.org/10.1080/09168451.2017.1362973 

Kyrkanides, S. et al. (2002), "Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury", Molecular Brain Research, Vol. 104/2, Elsevier, https://doi.org/10.1016/S0169-328X(02)00353-4. 

Lee, W. H. et al. (2010), "Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain", International Journal of Radiation Biology, Vol. 86/2, Informa, London, https://doi.org/10.3109/09553000903419346. 

Liu, J. L. et al. (2010), "Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo", Brain Research, Vol. 1316, Elsevier B.V., https://doi.org/10.1016/j.brainres.2009.12.055. 

Lodermann, B. et al. (2012), “Low dose ionising radiation leads to a NF-κB dependent decreased secretion of active IL-1β by activated macrophages with a discontinuous dose-dependency”, International Journal of Radiation Biology, Vol. 88/10, Informa, London, https://doi.org/10.3109/09553002.2012.689464 

Lumniczky, K., T. Szatmári and G. Sáfrány. (2017), "Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain", Frontiers in Immunology, Vol. 8, Frontiers Media S.A., Lausanne, https://doi.org/10.3389/fimmu.2017.00517. 

Moore, A. H. et al. (2009), "Sustained expression of interleukin-1β in mouse hippocampus impairs spatial memory", Neuroscience, Vol. 164/4, https://doi.org/10.1016/j.neuroscience.2009.08.073. 

Parihar, V. K. et al. (2018), "Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice", Experimental Neurology, Vol. 305, Elsevier B.V., https://doi.org/10.1016/j.expneurol.2018.03.009. 

Patterson, S. L. (2015), "Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity", Neuropharmacology, Vol. 96, Elsevier B.V., https://doi.org/10.1016/j.neuropharm.2014.12.020. 

Phatnani, H. and T. Maniatis. (2015), "Astrocytes in Neurodegenerative Disease: Table 1.", Cold Spring Harbor Perspectives in Biology, Vol. 7/6, Cold Spring Harbor Laboratory Press, https://doi.org/10.1101/cshperspect.a020628. 

Ramanan, S. et al. (2008), "PPARα ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways", Free Radical Biology and Medicine, Vol. 45/12, Elsevier B.V., https://doi.org/10.1016/j.freeradbiomed.2008.09.002. 

Scharpfenecker, M. et al. (2012), “The TGF-β co-receptor endoglin regulates macrophage infiltration and cytokine production in the irradiated mouse kidney”, Radiotherapy and Oncology, Vol. 105/3, Elsevier B.V., https://doi.org/10.1016/J.RADONC.2012.08.021 

Smith, J. A. et al. (2012), "Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases", Brain Research Bulletin, Vol. 87/1, Elsevier B.V., https://doi.org/10.1016/j.brainresbull.2011.10.004. 

van Neerven, S. et al. (2010), "Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid", Journal of Neuroimmunology, Vol. 229/1–2, Elsevier B.V., https://doi.org/10.1016/j.jneuroim.2010.08.005. 

Vezzani, A. and B. Viviani. (2015), "Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability", Neuropharmacology, Elsevier B.V.,  https://doi.org/10.1016/j.neuropharm.2014.10.027. 

Wang, Q. et al. (2020), "Radioprotective effect of flavonoids on ionizing radiation-induced brain damage", Molecules, MDPI AG, Basel, https://doi.org/10.3390/molecules25235719. 

Welser-Alves, J. V. and R. Milner. (2013), "Microglia are the major source of TNF-α and TGF-β1 in postnatal glial cultures; Regulation by cytokines, lipopolysaccharide, and vitronectin", Neurochemistry International, Vol. 63/1, Elsevier B.V., https://doi.org/10.1016/j.neuint.2013.04.007. 

Wu, Q. et al. (2017), “Macrophage biology plays a central role during ionizing radiation-elicited tumor response”, Biomedical Journal, Vol. 40/4, Elsevier, https://doi.org/10.1016/j.bj.2017.06.003 

Zhou, K. et al. (2017), "Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum", Scientific Reports, Vol. 7, Springer Nature, London, https://doi.org/10.1038/srep46181.