Aop: 464

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Toll-like receptor 4 (TLR4) activation in microglia leads to neurodegeneration via increase in neuroinflammation

Short name
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TLR4 activation in microglia leads to neurodegeneration

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Natalie Prowse, MSc. (natalie.prowse@carleton.ca)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Arthur Author

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on August 09, 2022 12:39

Revision dates for related pages

Page Revision Date/Time
Toll like receptor 4 Activation August 09, 2022 13:30
Induction, Nuclear Transcription Factor kappa B (NFkB) August 06, 2022 22:43
NLRP3 inflammasome activity, increased June 25, 2021 08:29
Increase, pro-inflammatory cytokines & reactive oxygen species August 01, 2022 13:42
N/A, Neurodegeneration (updated) August 09, 2022 13:04
Neuroinflammation July 15, 2022 09:54
TLR-4 Activation leads to Induction, NFkB August 09, 2022 00:59
TLR-4 Activation leads to Increase, pro-inflammatory cytokines & ROS August 11, 2022 00:49
Induction, NFkB leads to inflammasome activity, increased August 09, 2022 01:00
Increase, pro-inflammatory cytokines & ROS leads to N/A, Neurodegeneration (updated) August 09, 2022 12:39
Induction, NFkB leads to Increase, pro-inflammatory cytokines & ROS August 09, 2022 01:00
Increase, pro-inflammatory cytokines & ROS leads to Neuroinflammation August 09, 2022 01:13
Neuroinflammation leads to N/A, Neurodegeneration (updated) August 09, 2022 01:14
Lipopolysaccharride May 29, 2018 07:05
aminoalkyl glucosaminide phopsphates August 01, 2022 11:47
Pathogen Associated Molecular Patterns (PAMPs) March 26, 2021 04:14
Danger Associated Molecular Patters (DAMPs) March 26, 2021 04:13
Amyloid-beta protein 25-35 August 01, 2022 11:49
alpha-synuclein August 01, 2022 11:49
palmitic acid August 01, 2022 13:21
high mobility group box 1 August 07, 2022 15:50

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Inflammation-based neurodegeneration is a critical mediator in diseases of the central nervous system (CNS), that result in the degradation and loss of neurons and glia, ultimately leading to cognitive decline and death. Innate immune-mediated inflammation plays a role in CNS damage both acutely, such as in stroke or traumatic brain injury, and in a host of chronic neurodegenerative diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and amyotrophic lateral sclerosis (Glass et al., 2010)

As the primary immune cells of the brain, microglia are key mediators in the CNS inflammatory response (Block and Hong, 2005), primarily through pattern recognition receptors (PRRs) that have evolved to identify and target invading viruses and pathogens collectively known as pathogen-associated molecular patterns (PAMPS) and danger-associated molecular patterns (DAMPS) (Kofler and Wiley, 2011). Microglia also act as macrophages, responding to and cleaning up debris based on signals sent from dead and dying cells (Wolf et al., 2017).

A key activator of the inflammatory response in microglia is Toll-like receptor 4 (TLR4), which evolved in tetrapods primarily respond to bacterial invaders (Sepulcre et al., 2009; Schroder et al., 2012). While the canonical activator of TLR4 (and the most studied), is a component of the gram-negative bacterial cell wall, lipopolysaccharide (LPS) (Jerala, 2007; Park and Lee, 2013), recent research has identified many other molecules and environmental toxins that can activate TLR4, including misfolded protein aggregates such as amyloid-beta (Aβ) and alpha-synuclein, produced in Alzheimer’s and Parkinson’s disease, respectively (Fernandez-Lizarbe et al., 2009; Wong et al., 2009; Fellner et al., 2013; Liu et al., 2020; Romerio and Peri, 2020).  Termed “sterile inflammation”, there is mounting evidence that endogenous release of DAMPS from damaged and dying neurons results in chronic activation of TLR4 which can both cause and exacerbate neurodegeneration, both directly and through damage to blood-brain-barrier integrity (Graeber et al., 2011; Kuperberg and Wadgaonkar, 2017; Wilkins et al., 2017). In addition to disease-produced DAMPS, an increasing number of environmental toxins such as nanoparticles, have been found to produce or exacerbate TLR4-mediated inflammation (Bianchi et al., 2015).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Toll-like receptor 4 (TLR4) is present on a large number of cell types in the periphery of mammalian systems including those of the immune system, macrophages and epithelial cells. In the central nervous system, TLR4 is present on microglia and astrocytes, and to a lesser extent, neurons. Its primary role is to identify and defend the body against bacterial pathogens, however, overactivation can trigger signaling cascades that lead to run-away inflammation resulting in degeneration of cells and tissue. TLR4 agonists have been developed as vaccine adjuvants (Mata-Haro et al., 2007; Casella and Mitchell, 2008) and are under development for potential cancer treatments (Toroghian et al., 2022). Off-target effects of TLR-4 activation could have deleterious effects on brain and immune function and must be considered in any application. Importantly, TLR4 can be chronically activated by endogenous danger-associated molecular patterns (DAMPS) and pattern-associated molecular patterns (PAMPS) which can lead to "sterile inflammation" (Andersson and Tracey, 2011), while environmental toxins such as lead and titanium dioxide particles can augment and enhance TLR4 signaling (Luna et al., 2012; Bianchi et al., 2015). Finally, TLR4 signaling, alone or complexed with cluster of differentiation 36 (CD36) and TLR2, has been extensively studied in the context of neurodegeneration, particularly focussing on the role of chronically activated microglia in the aged and injured brain (Wendimu and Hooks, 2022).

The purpose of this AOP is to document the biology of this receptor signaling and implications of adverse outcomes, particularly through microglial activation, for potential future hazard identification that could lead to or exacerbate neurodegeneration.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

This AOP was developed based on prior knowledge and understanding of this pathway, supported by a large and well-documented breadth of research including systematic reviews on stressor-specific activation and identification of key events in the pathway. 

Key events such as "(188) Neuroinflammation" and "(352) N/A, Neurodegeneraton" have been reused, however, extensive changes were made to (352) and in the interests of not overwriting the existing without the author's permission, a new event "( 2039 ) N/A, Neurodegeneration (updated)" was created with additions to the prior event in red.  Ideally, these changes would be merged in the non-training wiki, with the original author's permission. 

Given the TLR4 activation pathways apply to a number of immune and epithelial cells, key events and relationships created specifically for this AOP were designed to be broadly applicable to a variety of cell types and initiating events.  A primary goal in developing this AOP is broad resusability of the KEs and KERs.  This AOP includes key events and key event relationships within the cellular pathway at a high level of detail as each of these events are possible targets for drug development.

Evidence was collected via comprehensive search using Web of Science and Pubmed to identify key research and domain applicablity pertaining to this AOP. Due to the overwhelming breadth and depth of research published with respect to TLR4 signaling, citations focused on high-quality reviews with high citation indexes, balanced with content pertaining to the most recent research available.

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 2033 Toll like receptor 4 Activation TLR-4 Activation
KE 2034 Induction, Nuclear Transcription Factor kappa B (NFkB) Induction, NFkB
KE 1895 NLRP3 inflammasome activity, increased inflammasome activity, increased
KE 2036 Increase, pro-inflammatory cytokines & reactive oxygen species Increase, pro-inflammatory cytokines & ROS
KE 188 Neuroinflammation Neuroinflammation
AO 2039 N/A, Neurodegeneration (updated) N/A, Neurodegeneration (updated)

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adults Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
human and other cells in culture human and other cells in culture High NCBI
mouse Mus musculus High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The overarching domain of applicability for this AOP is adult humans, though neuronal degeneration can occur at any age, given a severe enough stressor. While mice do not typically suffer from neurodegenerative diseases that afflict humans, much of the study of the neurodegenerative impacts of TLR4 signaling has been performed in mouse models.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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