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Neuroinflammation leads to Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory||adjacent||Moderate||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Increased glutamate leads to economic burden through reduced IQ and non-cholinergic mechanisms||adjacent||High||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages|
Key Event Relationship Description
Cells of the innate (microglia and astrocytes) and of the adaptive (infiltrating monocytes and lymphocytes) immune system of the brain have various ways to kill neighboring cells. This is in part due to evolutionary-conserved mechanisms evolved to kill virus-infected cells or tumor cells; in part it is a bystander phenomenon due to the release of mediators that should activate other cells and contribute to the killing of invading micro-organisms. An exaggerated or unbalanced activation of immune cells can thus lead to parenchymal (neuronal) cell death (Gehrmann et al., 1995). Mediators known to have such effects comprise components of the complement system and cytokines/death receptor ligands triggering programmed cell death (Dong and Benveniste, 2001). Various secreted proteases (e.g. matrix metalloproteases), lipid mediators (e.g. ceramide or gangliosides) or reactive oxygen species can contribute to bystander death of neurons (Chao et al., 1995; Nakajima et al., 2002; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013). The equimolar production of superoxide and NO from glial cells can lead to high steady levels of peroxynitrite, which is a very potent cytotoxicant (Yuste et al., 2015). Already stressed neurons, with an impaired anti-oxidant defence system, are more sensitive to such mediators (Xu et al., 2015). Healthy cells continuously display anti "eat-me" signals, while damaged and stressed neurons/neurites display "eat-me" signals that may be recognized by microglia as signals to start phagocytosis (Neher et al., 2012) or by astrocytes (Wakida et al., 2018; Byun and Chung, 2018; Gomez-Arboledas et al., 2018; Morizawa et al., 2017). Reactive astrocytes are also able to release neurotoxic molecules (Mena and Garcia de Ybenes, 2008; Niranjan, 2014). However, astrocytes may also be protective due to their capacity to quench free radicals and secrete neurotrophic factors. The activation of astrocytes may reduce neurotrophic support to neurons (for review, Mena and Garcia de Ybenes, 2008).
Evidence Collection Strategy
Evidence Supporting this KER
In vitro co-culture experiments have demonstrated that reactive glial cells (microglia and astrocytes) can kill neurons (Chao et al., 1995; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013) and that interventions with e.g. i-NOS inhibition can rescue the neurons (Yadav et al., 2012; Brzozowski et al., 2015). Drugs that block Toll like receptor pathways, which are expressed by glial cells have been proven to be protective by decreasing ROS and RNS production (Lucas et al., 2013).
Reactive microglia can remove synapses, a process known as synapse stripping (Banati et al., 1993; Kettenmann et al., 2013). Reactive astrocytes were also associated with neurite and synapse reduction (Calvo-Ochoa et al., 2014). Microglia can modulate synapse plasticity, an effect mediated by cytokines. During development, microglia can promote synaptogenesis or engulf synapses, a process known as synaptic pruning (for review, Jebelli et al., 2015). It is hypothesized that alterations in microglia functioning during synapse formation and maturation of the brain can have significant long-term effects on the final established neural circuits (for review, Harry and Kraft, 2012). The fact that astrocytes can receive and respond to the synaptic information produced by neuronal activity, owing to their expression of a wide range of neurotransmitter receptors, has given rise to the concept of tripartite synapse (for review, Perez-Alvarez and Araque, 2013; Bezzi and Volterra, 2001). Pro-inflammatory cytokines, such as TNF-a, IL-1b and IL-6, which are produced by reactive astrocytes, are on one side implicated in synapse formation and scaling, long-term potentiation and neurogenesis (for review, Bilbo and Schwartz, 2009) and on the other side can kill neurons (Chao et al., 1995; Kraft and Harry, 2011). Taken together, this suggests that neuron-glia interactions are tightly regulated and that an imbalance, such as increased or long-term release of these inflammatory mediators may lead to deleterious effects on neurons.
Uncertainties and Inconsistencies
In 3D rat brain cell-cultures, co-administration of the pro-inflammatory cytokine IL-6 (10 ng/ml) together with non-cytotoxic concentrations of MeHgCl (3 x 10-7 M) for 10 days protected from the mercury-induced decreased in MAP2 immunostaining, suggesting a positive effect of IL-6, in accord with its descibed trophic activity (Eskes et al., 2002).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most experimental evidences derived from mouse and rat studies.
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Bezzi, P., Volterra, A., 2001. A neuron-glia signalling network in the active brain. Curr Opin Neurobiol. 11, 387-94.
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Brzozowski MJ, Jenner P, Rose S. 2015. Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP(+)-induced neuronal toxicity. J Neural Transm 122(6): 779-788.
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Jebelli, J., et al., 2015. Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity? Ann N Y Acad Sci. 1351, 1-10.
Kettenmann, H., Kirchhoff, F., Verkhratsky, A., 2013. Microglia: new roles for the synaptic stripper. Neuron. 77, 10-8.
Kraft AD, Harry GJ. 2011. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International journal of environmental research and public health 8(7): 2980-3018.
Lucas, K., Maes, M., 2013. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 48, 190-204.
Matharasala, G., Samala, G., Perumal, Y., 2017. MG17, a novel triazole derivative abrogated neuroinflammation and related neurodegenerative symptoms in rodents. Curr Mol Pharmacol.
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Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. 2002. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem 80: 697-705.
Niranjan R. 2014. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes. Mol Neurobiol 49(1): 28-38.
Neher JJ, Neniskyte U, Brown GC. 2012. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Frontiers in pharmacology 3: 27.
Perez-Alvarez, A., Araque, A., 2013. Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets. 14, 1220-4.
Roda, E., et al., 2008. Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat. J Chem Neuroanat. 35, 285-94.
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Zhang, Y., Bolivar, V.J., Lawrence, D.A., 2013. Maternal exposure to mercury chloride during pregnancy and lactation affects the immunity and social behavior of offspring. Toxicol Sci. 133, 101-11.