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Relationship: 3357

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

Increase, Inflammation leads to Oligodendrocyte death, increased

Upstream event

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

Increase, Inflammation

Downstream event

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

Oligodendrocyte death, increased

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
Inhibition of neuropathy target esterase leading to delayed neuropathy via increased inflammation	adjacent	High		Brooke Bowe (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 Do not cite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

Term	Scientific Term	Evidence	Link
Mus musculus	Mus musculus		NCBI
Homo sapiens	Homo sapiens		NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

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

The relationship between these two events can vary depending on the type of cytokines or immune cells present in a certain tissue type, as some combinations induce cell death while others could be protective of cells. Nevertheless, inflammatory cytokines and leukocytes have been repeatedly noted to be able to enhance cell death across a variety of tissues throughout the body (Haanen & Vermes, 1995; van den Oever, Raterman, Nurmohamed, & Simsek, 2010; Göbel, et al., 2010).

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

Literature reviews were conducted by searching through databases including PubMed and Google Scholar. Search terms included “organophosphates”, “OPIDN”, “OPIDP”, and “delayed neuropathy” used in combination with a variety of phrases such as “enzyme inhibition”, “demyelination”, “demyelinating lesions”, “weakness”, and “endogenous substrate.” After establishment of the general outline for the AOP, search terms broadened to commonly include the words “neuropathy target esterase”, “irreversible aging”, “lysolecithin”, “lysophosphatidylcholine”, “inflammation”, “chemokines”, “surfactant”, “membrane disruption”, “oligodendrocyte susceptibility”, and “oligodendrocyte death.” Exclusion criteria included publications that focused on nervous tissue damage that did not involve changes to oligodendrocytes or myelin considering that this pathway focused on a single mechanism of a larger overall AOP network, and the goal was to specifically focus on progression of demyelination causing delayed neuropathy. Additional resources were also identified in the references of publications explored during database searches and were used to further develop KEs.

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

Strong ties have been made linking inflammation and oligodendrocyte death, either through the release of toxic by-products in the inflammatory response or through upregulation of receptors that help induce apoptosis or necrosis (Khanna, Ong, Bay, & Baeg, 2015). Oligodendrocytes appear to be particularly susceptible to death from inflammation due to a multitude of factors including their tendency to upregulate Fas, interferon‐gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) receptors along with major histocompatibility complex (MHC) class I molecules which are easily detected by T cells in inflammatory environments (Patel & Balabanov, 2012). Elevated apoptosis-causing cytokines from inflammation are ligands to the same corresponding receptors that have a tendency to be upregulated on oligodendrocytes, which implies that cytokines of the inflammatory response are central figures in instigating oligodendrocyte death.

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

Leukocytes are able to directly act on oligodendrocytes to stimulate cell death. Cell surface T cell receptors (TCR) and Fas ligand (FasL) on activated CD8+ and CD4+ T cells are able to directly bind to MHC class I molecules and Fas, respectively, on oligodendrocytes and lead to death by disrupting the membrane and inciting apoptosis directly (Patel & Balabanov, 2012; T cell-mediated cytotoxicity, 2001). Meanwhile, nearby macrophages can release harmful molecules such as oxygen- and nitric oxide-radicals which are particularly toxic to cellular mitochondria and contribute to injury (Patel & Balabanov, 2012; Bradl & Lassmann , 2010). In addition, elevated concentrations of certain cytokines such as TNF-α, interleukin-1 beta (IL-1β), IL-2, and IFN-γ can trigger cell death through increased binding to apoptosis-inducing receptors, as has been observed in oligodendrocyte cell lines and in animal studies (Buntinx, et al., 2004; Shi, et al., 2015; Ousman & David, 2001). Inhibition of some of these cytokines such as TNF-α in mouse cerebellar cultures resulted in finding that the reduced presence of this inflammatory mediator significantly decreased oligodendrocyte death, supporting the role it plays in the AOPxxx(535) (Di Penta, et al., 2013). As inflammation starts to occur, these key inflammatory players further potentiate each other, as both CD8+ and CD4+ T cells release additional IFN-γ, TNF-α, and TNF-β cytokines to further upregulate MHC class I molecules on oligodendrocytes and activate apoptosis receptors (Patel & Balabanov, 2012; T cell-mediated cytotoxicity, 2001).

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

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

References

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

Bradl, M., & Lassmann , H. (2010). Oligodendrocytes: biology and pathology. Acta Neuropathologica, 119, 37–53.

Buntinx, M., Moreels, M., Vandenabeele, F., Lambrichts, I., Raus, J., Steels, P., . . . Ameloot, M. (2004). Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-γ and TNF-α on apoptosis. Journal of Neuroscience Research, 76(6), 834-845.

Di Penta, A., Moreno, B., Reix, S., Fernandez-Diez, B., Villanueva, M., Errea, O., . . . Villoslada, P. (2013). Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation. PLOS One, 8(2), e54722.

El Waly, B., Buttigieg, E., Karakus, C., Brustlein, S., & Debarbieux, F. (2020). Longitudinal Intravital Microscopy Reveals Axon Degeneration Concomitant With Inflammatory Cell Infiltration in an LPC Model of Demyelination. Frontiers in Cellular Neuroscience, 14, 165.

Göbel, K., Melzer, N., Herrmann, A. M., Schuhmann, M. K., Bittner, S., Ip, C. W., . . . Wiendl, H. (2010). Collateral Neuronal Apoptosis in CNS Gray Matter. Glia, 58(4), 469-480.

Haanen, C., & Vermes, I. (1995). Apoptosis and inflammation. Mediators of Inflammation, 4, 5-15.

Khanna, P., Ong, C., Bay, B. H., & Baeg, G. H. (2015). Nanotoxicity: An Interplay of Oxidative Stress, Inflammation and Cell Death. Nanomaterials, 5(3), 1163-1180.

McMurran, C. E., Zhao, C., & Franklin, R. J. (2019). Toxin-Based Models to Investigate Demyelination and Remyelination. In D. A. Lyons, & L. Kegel, Oligodendrocytes: Methods and Protocols (pp. 377–396). Springer.

Ousman, S. S., & David, S. (2000). Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia, 30(1), 92-104.

Ousman, S. S., & David, S. (2001). MIP-1α, MCP-1, GM-CSF, and TNF-α Control the Immune Cell Response That Mediates Rapid Phagocytosis of Myelin from the Adult Mouse Spinal Cord. The Journal of Neuroscience, 21(13), 4649–4656.

Patel, J., & Balabanov, R. (2012). Molecular Mechanisms of Oligodendrocyte Injury in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. International Journal of Molecular Sciences, 13(8), 10647-10659.

Plemel, J. R., Michaels, N. J., Weishaupt, N., Caprariello, A. V., Keough, M. B., Rogers, J. A., . . . Yong, V. W. (2018). Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy. Glia, 66(2), 327-347.

Shi, H., Hu, X., Leak, R. K., Shi, Y., An, C., Suenaga, J., . . . Gao, Y. (2015). Demyelination as a Rational Therapeutic Target for Ischemic or Traumatic Brain Injury. Experimental Neurology, 272, 17–25.

T cell-mediated cytotoxicity. (2001). In C. Janeway, P. Travers, M. Walport, & S. Mark, Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science.

van den Oever, I. A., Raterman, H. G., Nurmohamed, M. T., & Simsek, S. (2010). Endothelial Dysfunction, Inflammation, and Apoptosis in Diabetes Mellitus. Mediators of Inflammation, 2010.