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Relationship: 2835

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, Pro-Inflammatory Mediators leads to Abnormal Neural Remodeling

Upstream event

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

Increase, Pro-Inflammatory Mediators

Downstream event

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

Abnormal Neural Remodeling

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	Under Review

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
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
Male	Moderate
Female	Low
Mixed	Moderate
Unspecific	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	Moderate
Not Otherwise Specified	Low
Juvenile	Low

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

Inflammatory mediators such as IL-1β, TNF-α, and IL-6 can affect the normal behavior of neuronal cells through alterations in: (a) the neuronal architecture and (b) synaptic activity. Overexpression of these pro-inflammatory mediators can disrupt the integrity of neurons through increased necrosis and demyelination, decreased neurogenesis, neural stem cell proliferation and synaptic complexity (Cekanaviciute et al., 2018; Fan & Pang, 2017). Structurally, the neuron is comprised of the cell body, dendrites, axon, and axon terminals, all of which are critical in the normal functioning of the central nervous system. Another important component of the neuron is its signaling properties, which uses chemical neurotransmitters to transfer messages in the synaptic cleft (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). Disruption to these structures or signaling properties results in abnormal neural remodeling.

Under physiological conditions, cytokine levels are low, but these can increase in response to various insults. Cytokines mediate immune response through ligand binding to cell surface receptors, which activate signaling cascades such as the JAK-STAT or MAPK pathways to produce or recruit more cytokines. Once organs initiate inflammatory reactions, the cytokines are capable of impairing neural function through direct effects on neurons or by indirect mechanisms mediated by microglia, astrocytes or vascular endothelial cells (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018).

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

Various studies provide support for the biological plausibility of the link between an increase in pro-inflammatory mediators and abnormal neural remodeling. It is known that cytokines and their receptors are constitutively expressed by neurons in the central nervous system, and even in normal or pathological states, these cytokines can be produced by individual cells and act on neurons. At the tissue level, the collective action and distribution of the cytokines can influence the overall inflammatory response within the brain tissue, impacting its function (Kishimoto et al., 1994). One important factor in the pathogenesis of neurotoxicity is the overexpression of pro-inflammatory mediators, or Th1-type, cytokines. These cytokines bind to their receptors to induce a conformational change, which triggers the activation of intracellular signaling pathways that alter cell structure and function (Mousa and Bakhiet, 2013). Several sources have reported a change in physical and electrophysiological properties of neurons in either whole-brain samples, specific brain regions such as the hippocampus or dentate gyrus, or neuronal cell cultures in response to increased expression of cytokines (Jenrow et al., 2013; Fan and Pang, 2017; Wong et al., 2004). The main cytokines presenting detrimental effects are IL-1β, TNF-α, and IL-6, which can cause alterations in neuronal architecture such as morphological changes in dendrites and synapses (Tang et al., 2017; Cekanaviciute et al., 2018; Shi et al., 2017). Many studies have also reported decreased proliferation and differentiation in progenitor cells, inhibited neural stem cell differentiation and decreased neurogenesis following increases in cytokines (Zonis et al., 2015; Wong et al., 2004; Tang et al., 2017). IL-6 can affect neurogenesis through various distinct mechanisms. One mechanism is through the stimulation of hypothalamic-pituitary-adrenal axis, which then increases circulating glucocorticoids. These steroids can then inhibit cell proliferation and neurogenesis in the dentate gyrus (Turnbull and Rivier, 1999; Gould et al., 1992; Cameron and Gould, 1994). Decreased neurogenesis in the hippocampus is also well documented as a result of pro-inflammatory mediators, and one possible mechanism for this detrimental effect is through the interaction of IL-1β and orphan nuclear receptor, TLX. This receptor is required to maintain the neural precursor cell pool in neurogenic brain regions, and it has been shown that IL-1β can reduce the expression of TLX and consequently cell proliferation (Ryan et al., 2013). TNF-α affects neuronal fate by interacting with its receptor, TNFR1, which is expressed on neural stem cells. It has been reported that TNFR1-mediated signaling pathway inhibits growth therefore, a reduction in neuron production after TNF-α injection (Chen and Palmer, 2013). A clear mechanistic relationship has not yet been established, although it is accepted that pro-inflammatory mediators can alter the structure and function of neurons.

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

The empirical evidence collected for this KER comes from both in vitro and in vivo studies. Abnormal neural remodeling can be defined by changes to the physical, functional and/or electrophysiological properties of neurons. Most of the evidence examines effects of inflammation induced by either dextran sodium sulfate (DSS) treatment, seizure induction, heavy ion or X-ray irradiation at higher doses (>5 Gy) and varying dose-rates from 78.0 cGy/min to 3.2 Gy/min, or lipopolysaccharide injection on both in vivo and in vitro rodent models. Injections or treatments with pro-inflammatory cytokines were also used. These studies provide evidence to support a causal association between an increase in pro-inflammatory mediators and decreased neurogenesis, but also provide evidence of reduced neuronal signaling, neural stem cell and progenitor cell proliferation, as well as a change in overall neuronal shape (Zonis et al., 2015; Vallieres et al., 2002; Green et al., 2012; Wu et al., 2012; Chen and Palmer, 2013; Saraiva et al., 2019; Zhang et al., 2017; Dong et al., 2015; Kalm et al., 2013; Wong et al., 2004; Jenrow et al., 2013; Liu et al, 2010).

Time Concordance

Multiple studies suggest time-concordant relationship between increases in pro-inflammatory mediators leading to abnormal neural remodeling. The proliferation and survival of stem and progenitor cells, collectively known as neural precursor cells, was decreased or inhibited in response to increase pro-inflammatory cytokines at 4 days, 7 days and 1-month post-treatment (Zonis et al., 2015; Wong et al., 2004, Green et al., 2012; Ryan et al., 2013; Vallieres et al., 2002). Various studies also report a reduction in neurogenesis in the hippocampus and dentate gyrus 1-month post-treatment that was well-correlated with increased IL-1β, TNF-α, and IL-6 levels (Zonis et al., 2015; Vallieres et al., 2002; Wu et al., 2012; Chen and Palmer, 2013). In addition to a significant decrease in neurogenesis 1-month post-treatment, a study found that sustained IL-1β expression caused a significant reduction in neurogenesis that persisted for 3 months (Wu et al., 2012). Another study observed that X ray-induced increases in IL-1β and TNF-α at three and six hours resulted in a time-dependent decrease in DCX+ cells, a marker for neurogenesis, which persisted for 2 weeks. This was seen after a single dose of 10 Gy (Dong et al., 2015). Thus, these studies provide evidence to support time concordance of the relationship using both in vivo and in vitro models.

Dose Concordance

No available data.

Incidence Concordance

No available data.

Essentiality

Several treatments that directly alter pro-inflammatory mediators preserve neuronal integrity in the dentate gyrus and positively modulate hippocampal neurogenesis. The treatments included MW-151, a selective inhibitor of pro-inflammatory cytokine production and Kukoamine A, an alkaloid that inhibits neuronal oxidative stress and hippocampal apoptosis (Jenrow et al., 2013; Zhang et al., 2017). Another treatment used was histamine, which has been shown to ameliorate the loss of neuronal complexity and synaptic plasticity (Saraiva et al., 2019). Multiple studies use cytokine receptor antagonists or knock-out key receptors to block the effects of IL-1β, TNF-α, and CCL2, which have preserves neuron survival (Green et al., 2012; Ryan et al., 2013; Wu et al., 2012; Chen and Palmer, 2013). Another knockout model of complement component 3 (C3) have also been used to demonstrate essentiality. C3 is a central molecule in the complement cascade, and its roles include microglia-mediated synapse elimination. C3 knockout models have been shown to cause reduced pro-inflammatory cytokines, increased synaptic number, reduced neuron loss and synaptic morphology impairment (Shi et al., 2017).

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

Various in vitro studies have reported a stimulation of neural precursor cell proliferation and differentiation or increased neurogenesis by different cytokines such as IL-6 and IFN-γ (Islam et al., 2009; Wong et al., 2004). Another study found increased proliferation within the hippocampus after repeated IL-6 and IL-1β infusion (Seguin et al., 2009). Although a clear mechanism has not yet been elucidated, it is thought that these cytokines have contradictory effects from the differential activation of various signaling cascades (Borsini et al., 2015). For example, hyper-IL-6, a fusion of IL-6 and IL-6 receptor, was found to increase neurogenesis through the activation of MAPK/CREB (mitogen-activated protein kinase/cAMP response element binding protein) cascade (Islam et al., 2009).
It has also been reported that TNF-α exhibits neuroprotective effects as their transmembrane receptors can influence different signaling pathways (Figiel, 2008; Masli & Turpie, 2009)
Kalm et al. (2013) found a higher inflammatory response in lipopolysaccharide (LPS) treated females compared with males after irradiation. Specifically, increased levels of pro-inflammatory cytokines IL-1β, IL-12, and IL-17, as well as pro-inflammatory chemokines CCL4, CCL3 and CCL2 were detected relative to vehicle-treated animals and LPS-treated males. This was associated with a 32% decrease in DCX+ cells, a marker for neurogenesis, in females. However, in LPS-treated males, a 64% reduction in DCX+ cells compared to vehicle-treated males following irradiation was reported (Kalm et al., 2013). Further research is required to elucidate the exact effects of increased pro-inflammatory mediators on neural integrity between males and females.

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 Therapy	MW01-2-151SRM (MW-151) – water soluble, nontoxic, bioavailable compound that mitigates pro-inflammatory cytokine production, glial activation and inflammation in rat hippocampus.	MW-151 reduced the neuroinflammation caused by 10 Gy of heavy ion exposure, thus preserving the integrity of neurogenic signaling in the dentate gyrus.	Jenrow et al., 2013
Genetic Manipulation	IL-1 receptor antagonist to prevent the interaction between IL-1β with IL-1R1.	After 7 days in vitro, IL-1β significantly decreased the percentage of DCX-positive neurons, but pre-treatment and subsequent co-treatment with IL-1RA abolished this anti-neurogenic effect of IL-1β.	Green et al., 2012
Neuromodulator	Histamine – an endogenous amine that can regulate both brain inflammation and neurogenesis.	Histamine treatment significantly increased the total number cells, positively modulates hippocampal neurogenesis, ameliorates the loss of neuronal complexity of hippocampal neuroblasts and reverts synaptic plasticity loss caused by LPS.	Saraiva et al., 2019
Drug	Tamoxifen – synthetic, non-steroidal estrogen receptor modulator with anti-inflammatory and neuroprotective properties.	Tamoxifen decreased the production of inflammatory cytokines released from irradiated microglia, attenuating glial activation and decreasing neuronal apoptosis.	Liu et al., 2010
Drug	Kukoamine A (KuA) – alkaloid extracted from traditional Chinese herb cortex lycii radicis that has been previously reported to have antioxidant properties.	KuA inhibited radiation-induced increases in pro-inflammatory cytokines, alleviated the activation of hippocampal microglia and ameliorated the suppression of hippocampal neurogenesis.	Zhang et al., 2017
Genetics	Polymorphism that increases the expression of APOE4 increases the risk of developing Alzheimer’s diseases, which generally consists of a decline in memory, thinking and language.	In homozygous human APOE4 knock-in mice, a dramatic increase in pro-inflammatory cytokines TNF-α, IL-1β and IL-6 was seen after LPS injection compared to the APOE2 and APOE3 alleles, suggesting that APOE4 is implicated in a greater inflammatory response.	Hunsberger et al., 2019; Zhu et al., 2012

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

The table below provides some representative examples of quantitative linkages between the two key events as presented in the paper. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated.

Time Concordance

Reference	Experiment Description	Results
Zonis et al., 2015	In vitro. Adult female C57Bl/6 mice were treated with 3% wt/vol dextran sodium sulfate (DSS) using a multiple-cycle administration for up to 26 days. ELISA and qRT-PCR were used to measure cytokine levels in neural precursor cells and neural progenitor cell cultures. Western blot and immunostaining were used to measure Ki67 (neuronal cell proliferation marker), DCX (marker for neurogenesis), BLBP (marker for stem/early progenitor cells) and nestin (neural stem cell marker and involved in radial growth of axons). p21 (regulator of cell cycle progression at G1 and S phase) was also measured using these methods.	Neural precursor cells (NPCs) treated with 50 ng/mL of IL-6 led to a decline in the % of neuroblasts, with declines from 41% ± 6.4% in untreated cells to 22.39% ± 5.2% in IL-6-treated cells). Thus, decreasing neurogenesis was observed in in NPCs after DSS treatment. Chronic intestinal inflammation (29 days post-treatment) reduced hippocampal neurogenesis. Evidence has highlighted that IL-1β and TNF-α mRNA levels were increased more than 2-fold, as well as a fourfold increase in p21 mRNA levels, which were accompanied by an approximate 2-fold down-regulation of progenitor cell proliferation and neurogenesis. Protein levels of IL-1β and TNF-α were not assessed.
Jenrow et al., 2013	In vivo. Adult male Fischer 344 rats were exposed to 10 Gy of whole-brain irradiation (WBI) using a 137Cs irradiator at a dose rate of 3.2 Gy/min. Rats also underwent mitigating therapy with MW01-2-151SRM (MW-151), a selective inhibitor of β amyloid-induced glial pro-inflammatory cytokine production that was initiated 24 h post-WBI and was continued for 28 days post-WBI by daily injection. Immunofluorescence assays for cell proliferation and neurogenesis were performed at 2 months and for neuroinflammation at 2 and 9 months post-WBI.	MW-151 mitigated radiation-induced neuroinflammation, measured by OX-6+ cell densities, an indicator of pro-inflammatory level of activation, at 2- and 9-months post-irradiation. The 10 Gy group had mean OX-6+ cell densities of 1,966 (±218) and 1,493 (±270) cells/mm3, respectively. In the 10 Gy MW-151 group, the mean OX-6+ cell densities were significantly reduced to 849 (±350) and 437 (±119) cells/mm3, respectively. In addition, 2 months post-irradiation, the mean DCX+ cell density, a marker for neurogenesis, was 1,375 (±535) cells/mm3 in the 10 Gy group, but was significantly increased to 4,702 (±622) cells/mm3 after MW-151 therapy.
Vallieres et al., 2002	In vitro. Seizure was induced in transgenic mice expressing IL-6 under control of the glial fibrillary acidic protein (GFAP) promoter. Bromodeoxyuridine (BrdU) assay and immunofluorescence was used to detect proliferating neural progenitor cells and fluoro-jade staining was used to detect degenerating neurons.	IL-6 compromised proliferation, survival, and differentiation of hippocampal progenitor cells when expressed over the long term (31 days) in young adult transgenic mice expressing the IL-6 transgene, causing a 63% decrease in the production rate of new neurons. The BrdU assay revealed a 27% reduction in progenitor cell proliferation, 53% reduction in progenitor cell survival in the dorsal hippocampus.
Wong et al., 2004	In vitro. Neural stem cell lines derived from adult C57BL/6 mice were allowed to proliferate and differentiate for 1 h to 3 days in the presence of IFN-γ and TNF-α. Proliferation and cytotoxicity assays were used to assess neural stem cell survival and their ability to differentiate and proliferate.	IFN-γ (100 U/mL) and TNF-α (10 ng/mL) inhibited neural stem cell proliferation. The reduction was first significant at 4 days when control cells began to proliferate rapidly, and until day 6, control cells continued to proliferate while IFN-γ and TNF-α inhibited proliferation.
Green et al., 2012	In vitro. Rat hippocampal NPC cultures were treated with IL-1β (10 ng/mL) in the presence or absence of IL-1 receptor antagonist (IL-1RA), which prevents the interaction of IL-1β with IL-1R1. Cell proliferation analysis was performed, and RT-PCR and immunoblotting were used to measure DCX and cytokines. MTT assay was used to assess cell viability.	Treatment with 10 ng/mL of IL-1β significantly decreased neurosphere circumference in a time-dependent manner. Compared to untreated cultures, a difference was seen at day 4, which continued until day 7. Neural integrity was assessed by examining the neural cell viability and proliferation IL-1β treatment for 24 hours after 4 days in vitro significantly decreased cell proliferation. IL-1β treatment for 7 days in vitro caused a significant decrease in cell viability compared to untreated cultures.
Wu et al., 2012	In vitro. Wild-type and IL-1βXAT C57BL/6 mice were exposed to Cre recombinase to induce IL-1β overexpression. Immunohistochemistry was used to measure IL-1β and DCX, a marker for migrating neuroblasts and neurogenesis.	There was a significant effect of sustained IL-1β overexpression on adult neurogenesis one month after injection. A 94% decrease in migrating neuroblasts and neurogenesis was found, mirroring the pattern of neuroinflammation. 3 months post-injection, there was also an 87% reduction in neurogenesis.
Chen and Palmer, 2013	In vitro. Microglial cultures isolated from neonatal pups of C57BL/6 mice were treated with 1 μg/mL LPS, then incubated in neural stem cell (NSC) differentiation medium. The conditioned medium was then collected and applied to NSCs. Immunohistochemistry was used to measure cytokine levels and DCX, a marker for neurogenesis.	After 72 h, neurogenesis significantly reduced in the differentiation culture after TNF-α injection of 20 ng/mL. One month after injection, proliferation and survival of endogenous neural stem cells decreased, as well as a reduction in neurogenesis.
Saraiva et al., 2019	In vitro. C57BL/6J male mice were injected with 1 or 2 mg/kg LPS. Histamine was also injected in the hippocampal dentate gyrus. The BrdU assay was used to quantify proliferating cells, while immunohistochemical analysis and western blot was used to measure IL-1β and DCX.	In mice exposed to LPS, histamine significantly increased the total amount of proliferative cells. Mice exposed to 1 mg/kg of LPS had 98.8 ± 4.7 BrdU+ cells, a marker for proliferating cells, whereas 1 mg/kg of LPS + His had 197.6 ± 28.2 BrdU+ cells. 2 mg/kg of LPS yielded 96.7 ± 9.7 BrdU+ cells and 2 mg/kg of LPS + Histamine had 154.1 ± 23.8 BrdU+ cells. Histamine was also able to revert the LPS-induced loss of neuronal volume from 238.6 ± 19.7 (1 mg/kg LPS) to 331.1 ± 33.4 (1 mg/kg LPS + His) µm3. And 248.7 ± 18.8 (2 mg/kg LPS) to 334.3 ± 24.8 (2 mg/kg LPS + His) µm3. Postsynaptic density protein 95 (PSD-95) levels were also elevated due to histamine treatment (2 mg/kg LPS, 55.8 ± 9.9; 2 mg/kg LPS + His, 110.1 ± 12.9).
Ryan et al., 2013	In vitro. Adult Sprague Dawley rat dentate gyrus NPC cultures were prepared and treated with IL-1β (100 ng/mL) for 7 days. Immunohistochemistry was used to detect NPCs, proliferating cells and newly born cells.	24 h after IL-1β treatment (100 ng/mL), there was no difference in proliferating neural cells relative to untreated cells. However, at 7 days post-treatment, there was a significant reduction in proliferating neural cells. There was also a decrease in neurogenesis.
Dong et al., 2015	In vitro. The mouse microglial cell line, BV-2, were irradiated with a single 16 Gy dose of X-rays, then assessed at various time points up to 6 weeks. ELISA was used to measure levels of IL-1β and TNFα, whereas immunohistochemical staining was used to detect DCX+ cells.	DCX+ cells, a marker of neurogenesis, were significantly reduced at 6 h until 2 weeks post-irradiation, which was accompanied by increased levels of IL-1β and TNF-α. TNF-α levels peaked at 3 h post-irradiation, decreased at 6 h, then increased in a time-dependent manner until 2 weeks. IL-1β levels increased in a time-dependent manner until peaking at 72 h, then spiked again at 6 weeks.

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

Evidence for this relationship comes from rat and mouse models. There is in vivo evidence in both male and female animals, with more evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models.

References

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

Borsini, A. et al. (2015), "The role of inflammatory cytokines as key modulators of neurogenesis", Trends in Neurosciences, Vol. 38/3, Elsevier, Amsterdam, https://doi.org/10.1016/j.tins.2014.12.006.

Cameron, H. A. and E. Gould. (1994), "Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus", Neuroscience, Vol. 61/2, Elsevier, Amsterdam, https://doi.org/10.1016/0306-4522(94)90224-0.

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), "Central nervous system responses to simulated galactic cosmic rays", International Journal of Molecular Sciences, Vol. 19/11, Multi-Disciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms19113669.

Chen, Z. and T. D. Palmer. (2013), "Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis", Brain, Behavior, and Immunity, Vol. 30, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.bbi.2013.01.083.

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, Taylor & Francis Group, London, https://doi.org/10.3109/09553002.2014.988895.

Fan, L. W. and Y. Pang. (2017), "Dysregulation of neurogenesis by neuroinflammation: Key differences in neurodevelopmental and neurological disorders", Neural Regeneration Research, Vol. 12/3, Wolters Kluwer, Alphen aan den Rijn, https://doi.org/10.4103/1673-5374.202926.

Figiel, I. (2008) “Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain.” Acta neurobiologiae experimentalis,Vol. 68/4, Nencki Institute of Experimental Biology, Warsaw, 526-34, https://doi.org/10.55782/ane-2008-1720

Gould, E. et al. (1992), "Adrenal hormones suppress cell division in the adult rat dentate gyrus", The Journal of Neuroscience, Vol. 12/9, Society for Neuroscience, Washington, https://doi.org/10.1523/JNEUROSCI.12-09-03642.1992.

Green, H. F. et al. (2012), "A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells", Molecular and Cellular Neuroscience, Vol. 49/3, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.mcn.2012.01.001.

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

Hunsberger, H. C. et al. (2019), "The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions", Neuronal Signaling, Vol. 3/2, Portland Press, London, https://doi.org/10.1042/NS20180203.

Islam, O. et al. (2009), "Interleukin-6 and Neural Stem Cells: More Than Gliogenesis", (C.-H. Heldin, Ed.)Molecular Biology of the Cell, Vol. 20/1, The American Society for Cell Biology, Rockville, https://doi.org/10.1091/mbc.e08-05-0463.

Jenrow, K. A. et al. (2013), "Selective Inhibition of Microglia-Mediated Neuroinflammation Mitigates Radiation-Induced Cognitive Impairment", Radiation Research, Vol. 179/5, Bio One, Washington, https://doi.org/10.1667/RR3026.1.

Kalm, M., K. Roughton and K. Blomgren. (2013), "Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation", Cell Death & Disease, Vol. 4/12, https://doi.org/10.1038/cddis.2013.482.

Kishimoto, T., T. Taga and S. Akira. (1994), "Cytokine signal transduction", Cell, Vol. 76/2, Elsevier, Amsterdam, https://doi.org/10.1016/0092-8674(94)90333-6.

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, Amsterdam, https://doi.org/10.1016/j.brainres.2009.12.055.

Masli, S, and B. Turpie. (2009) “Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells.” Immunology, Vol. 127/1 (2009), John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1111/j.1365-2567.2008.02933.x

Mousa, A. and M. Bakhiet. (2013), "Role of Cytokine Signaling during Nervous System Development", International Journal of Molecular Sciences, Vol. 14/7, Multi-Disciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms140713931.

Prieto, G. A. and C. W. Cotman. (2017), "Cytokines and cytokine networks target neurons to modulate long-term potentiation", Cytokine & Growth Factor Reviews, Vol. 34, Elsevier, Amsterdam, https://doi.org/10.1016/j.cytogfr.2017.03.005.

Ryan, S. M. et al. (2013), "Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation", Brain, Behavior, and Immunity, Vol. 33, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbi.2013.03.005.

Saraiva, C. et al. (2019), "Histamine modulates hippocampal inflammation and neurogenesis in adult mice", Scientific Reports, Vol. 9/1, Springer Nature, Berlin, https://doi.org/10.1038/s41598-019-44816-w.

Seguin, J. A. et al. (2009), "Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.", Neuropsychiatric disease and treatment, Vol. 5, Dove Press Ltd., Macclesfield, http://www.ncbi.nlm.nih.gov/pubmed/19557094.

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