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Relationship: 2832

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

Energy Deposition leads to Tissue resident cell activation

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 Moderate 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

Deposition of energy refers to particles that have sufficient energy to penetrate biological tissue leading to ionization events that can break water molecules and form free radicals. These can damage sensitive macromolecules such as DNA, protein and lipids (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Ionization events occur from many types of radiation including, X-rays, gamma-rays, alpha particles, beta particles, heavy ions, and neutrons. X-rays and gamma rays induce sparse ionization events and energy is exponentially absorbed by tissues. Conversely, energetic charged particles can cause dense ionization events, leading to clustered damage and secondary ionization events (Niemantsverdriet et al., 2012). 

When sufficient energy is deposited it can damage the cellular environment; this releases danger signals either passively when the ionization events induce cell death, or actively by cells undergoing life threatening stress (Denning et al., 2019; Vénéreau, Ceriotti & Bianchi, 2015). These signaling molecules, such as alarmins or damage-associated molecular pattern molecules (DAMPs),  promote an inflammatory and regenerative environment by activating tissue resident cells (Chen, Oyarzabal & Hong, 2016; Vénéreau, Ceriotti & Bianchi, 2015). Resident immune cells, such as macrophages and dendritic cells, use pattern recognition receptors on their surfaces to detect alarmins and DAMPs which initiate their activation and proliferation (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Activated cells can then regulate the recruitment of circulating immune cells and initiate inflammation to remove damaged cells, eliminate harmful stimuli, and promote tissue repair (Schaue et al., 2015; Roh & Sohn, 2018).  However, uncontrolled inflammation can then lead to a state of disease progression. 

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

There is strong biological evidence and mechanistic understanding linking deposition of energy to tissue resident activation. It is widely accepted that deposition of energy can cause the activation of resident tissue cells (Di Maggio et al., 2015; Frey et al., 2015; Mavragani et al., 2016; Multhoff & Radons, 2012; Pinto et al., 2016; Rodel et al., 2012; Schaue et al., 2015; Yahyapour et al., 2018; Zhao & Robbins, 2009; Rienecker et al., 2021). Ionization of local tissue leads to direct tissue damage, reduced cellular homeostasis, genotoxic stress, and oxidative stress (Mavragani et al., 2016; Yahyapour et al., 2018). This damage can initiate tissue resident cell activation (Davies et al., 2013; Langston, Shibata & Horng, 2017; Rienecker et al., 2021). Primary damage and follow-on free-radical events typically occur within microseconds, but the inflammatory response carries on the damage through waves of reactive oxygen species generation as well as cytokine and chemokine release (Schaue et al., 2015). The resultant loss of cellular homeostasis, as well as primary and secondary cellular damage leads to the release of DAMPs (Mavragani et al., 2016; Yahyapour et al., 2018). Resident cells then use pattern recognition receptors to detect DAMPs resulting in their activation through a series of intracellular signaling cascades (Mavragani et al., 2016; Yahyapour et al., 2018). 

There are many resident cells that become activated in response to radiation damage including lymphocytes, neutrophils, endothelial cells, and dendritic cells. Among the resident cells, macrophages are present in virtually all tissues and are the first line of defense against foreign pathogens and stressors. Resident macrophages have a ramified morphology with long, dynamic processes and are constantly surveying for signals of injury or infection (Betlazar et al., 2016; Paladini et al., 2021). They are also scavenger cells which engulf metabolites and debris from surrounding apoptotic cells to maintain healthy organs and tissues. When damage is detected, local macrophages become activated and move to the site of injury, where they signal other immune cells and release cytokines, chemokines, and other soluble molecules to mediate wound healing and initiate an inflammatory response (Hladik & Tapio, 2016; Paladini et al., 2021; Yahyapour et al., 2016; Rienecker et al., 2021). Resident macrophages detect endogenous cellular components released from damaged, stressed, or dying cells through pattern recognition receptors such as toll-like receptors (TLRs) (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2016). TLRs can detect a wide variety of DAMPs including those potentially formed by deposition of energy ( i.e., oxidized DNA, uric acid, ATP and high-mobility group box 1 protein) (Yahyapour et al., 2016). When TLRs detect DAMPs in the extracellular environment, they initiate intracellular signaling cascades that lead to the nuclear translocation of transcription factors, such as nuclear factor-κB (NF-κB), to induce the production of proinflammatory cytokines and chemokines (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2018). The resident macrophages also initiate granulocyte-macrophage colony formation and recruitment of early myeloid progenitors to the site of injury (Schaue et al., 2015). 

This response has been shown to occur across organs and tissue types using the same underlying mechanisms (Chen, Oyarzabal & Hong, 2016, Mavragani et al., 2016, Schaue et al., 2015). However, tissues are distinct in the types of activated cells and the resulting inflammatory responses. For example, the liver hosts the largest population of macrophages (Kupper cells) and is enriched with T lymphocytes or natural killer cells (Szabo, Mandrekar & Dolganiuc, 2007). Local Kupper cells use pattern recognition receptors to detect local radiation damage which leads to their activation (Szabo, Mandrekar & Dolganiuc, 2007). Activated cells secrete proinflammatory mediators, recruit macrophages and regulate the response of local T lymphocytes (Szabo, Mandrekar & Dolganiuc, 2007). In the lungs, radiation damage is first detected by local epithelial cells that produce pro-inflammatory mediators including cytokines and reactive oxygen species (Chen et al., 2018). These mediators stimulate mucus secretion by goblet cells and recruit macrophages and dendritic cells to initiate inflammation (Moldoveanu et al., 2009). In some organs, such as the brain, resident immune cells are abundant because the organ is separated from the immune system by the blood brain barrier to protect it from infection by foreign cells (Banks & Erickson, 2010). It has been shown that brain exposure to ionizing radiation can initiate activation of other types of resident immune cells, such as microglia and astrocytes (Betlazar et al., 2016). Microglial cells are the first line of defense in response to radiation damage and become activated in response to DAMPs released from local damaged cells (Betlazar et al., 2016). Microglia cells release pro-inflammatory mediators to regulate an inflammatory response and recruit additional immune cells to the site of injury (Betlazar et al., 2016). Microglia can subsequently induce astrocyte activation via the COX-2 pathway in the presence of a stressor (Betlazar et al., 2016; Cucinotta et al., 2014; Paladini et al., 2021). When damage is detected, astrocytes proliferate and form scar tissue via reactive gliosis (Makale 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
  • There is no consensus about sex-related responses to radiation exposure and the resulting activation of tissue resident cells. Krukowski et al. (2018a) and Parihar et al. (2020) found that female mice were immune to the effects of 0.3 and 0.5 Gy radiation on cell activation, while Raber et al. (2019) found that only female mice showed increased activated cells after 2 Gy. 

  • A large amount of uncertainty surrounds the impact of low-dose ionizing radiation on tissue resident cell activation. More evidence is required to determine the relationship between ionizing radiation at doses < 1 Gy and tissue-resident cell activation. 

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  

Sex 

Male and female mice had different responses in tissue resident cell activation following irradiation. 

Male mice typically showed an increase in microglia activation, while female mice showed no significant changes. However, not all studies found this trend. 

Krukowski et al., 2018a; Parihar et al., 2020; Raber et al., 2019 

Drug 

Colony stimulating factor 1 receptor inhibitor PLX5622 (eliminates microglia). 

PLX5622 reduced the number of activated microglia. 

Acharya et al., 2016; Allen et al., 2020; Krukowski et al., 2018b 

Drug 

P2X7 receptor (associated with microglial activation) inhibitor Brilliant Blue G. 

Treatment attenuated the increase in microglial activation both in vivo and in vitro after irradiation. 

Xu et al., 2015 

Age 

10-day-old and 10-week-old mice. 

At 10 days old, irradiated mice showed increased glial activation, while at 10 weeks old they did not show significant changes in activation. 

Casciati et al., 2016 

 7-, 17- and 27-month-old mice. 

Activation of microglia after irradiation decreased as age was increased. 

Hua et al., 2012 

Genetics 

Extracellular SOD knockout mice. 

Microglial activation was increased more in SOD knockout mice than wild-type mice after 5 Gy gamma rays. 

Rola et al., 2007 

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

N/A

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

The domain of applicability is related to any vertebrates and invertebrates with an innate immune system regardless of sex (Beck & Habicht, 1996, Sonetti et al., 1994, Rowley, 1996). The deposition of energy is most detrimental in utero because tissue resident cells and their pro-inflammatory responses can cause permanent tissue damage  (Heiervang et al., 2010, McCollough et al., 2007, Kannan et al., 2007). 

References

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

Acharya, M. M. et al. (2016), "Elimination of microglia improves cognitive function following cranial irradiation", Scientific Reports, Vol. 6/1, Nature Publishing Group, https://doi.org/10.1038/srep31545. 

Allen, B. D. et al. (2020), "Mitigation of helium irradiation-induced brain injury by microglia depletion", Journal of Neuroinflammation, Vol. 17/1, Nature, https://doi.org/10.1186/s12974-020-01790-9. 

Al Zaman, M. A. and Q. M. R. Nizam. (2022), "Study on Shielding Effectiveness of a Combined Radiation Shield for Manned Long Termed Interplanetary Expeditions", Journal of Space Safety Engineering, Vol. 9/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.jsse.2021.12.003. 

Banks, W. A. and M. A. Erickson. (2010), "The blood–brain barrier and immune function and dysfunction", Neurobiology of Disease, Vol. 37/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.nbd.2009.07.031. 

Beck, G. and G. S. Habicht. (1996), "Immunity and the Invertebrates", Scientific American, Vol. 275/5, Nature, https://doi.org/10.1038/scientificamerican1196-60. 

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

Capri, M. et al. (2019), "Recovery from 6‐month spaceflight at the International Space Station: muscle‐related stress into a proinflammatory setting", The FASEB Journal, Vol. 33/4, Wiley, https://doi.org/10.1096/fj.201801625R. 

Casciati, A. et al. (2016), "Age-related effects of X-ray irradiation on mouse hippocampus", Oncotarget, Vol. 7/19, https://doi.org/10.18632/oncotarget.8575. 

Chen, H. et al. (2016), "Delayed activation of human microglial cells by high dose ionizing radiation", Brain Research, Vol. 1646, Elsevier, Amsterdam, 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, https://doi.org/10.18632/oncotarget.23208. 

Chen, S.-H., E. A. Oyarzabal and J.-S. Hong. (2016), "Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration", Current Opinion in Pharmacology, Vol. 26, Elsevier, Amsterdam, https://doi.org/10.1016/j.coph.2015.10.001. 

Chiang, C. S., W. H. McBride and H. R. Withers. (1993), "Radiation-induced astrocytic and microglial responses in mouse brain", Radiotherapy and Oncology, Vol. 29/1, Elsevier, Amsterdam, https://doi.org/10.1016/0167-8140(93)90174-7. 

Cucinotta, F. A. et al. (2014), "Space radiation risks to the central nervous system", Life Sciences in Space Research, Vol. 2, Elsevier, Amsterdam, https://doi.org/10.1016/j.lssr.2014.06.003. 

Cummings, P. et al. (2007), "High-energy (hze) radiation exposure causes delayed axonal degeneration and astrogliosis in the central nervous system of rats", Gravitational and Space Research, Vol. 20/2. 

Davies, L. C. et al. (2013), "Tissue-resident macrophages", Nature Immunology, Vol. 14/10, Nature, https://doi.org/10.1038/ni.2705. 

Denning, N.-L. et al. (2019), "DAMPs and NETs in Sepsis", Frontiers in Immunology, Vol. 10, Frontiers, https://doi.org/10.3389/fimmu.2019.02536. 

Dey, D. et al. (2020), "Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy", Radiation Research, Vol. 193/5, BioOne, https://doi.org/10.1667/RR15540.1. 

Di Maggio, F. M. et al. (2015), "Portrait of inflammatory response to ionizing radiation treatment", Journal of Inflammation, Vol. 12/1, Nature, https://doi.org/10.1186/s12950-015-0058-3. 

Frey, B. et al. (2015), "Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases", Cancer Letters, Vol. 368/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2015.04.010. 

Heiervang, K. S. et al. (2010), "Effect of low dose ionizing radiation exposure in utero on cognitive function in adolescence", Scandinavian Journal of Psychology, Vol. 51/3, Wiley, https://doi.org/10.1111/j.1467-9450.2010.00814.x. 

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

Hua, K. et al. (2012), "Regionally Distinct Responses of Microglia and Glial Progenitor Cells to Whole Brain Irradiation in Adult and Aging Rats", PLoS ONE, Vol. 7/12, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0052728. 

Hwang, S. Y. et al. (2006), "Ionizing radiation induces astrocyte gliosis through microglia activation", Neurobiology of Disease, Vol. 21/3, Academic Press, https://doi.org/10.1016/j.nbd.2005.08.006. 

Kannan, S. et al. (2007), "Microglial Activation in Perinatal Rabbit Brain Induced by Intrauterine Inflammation: Detection with 11C-(R)-PK11195 and Small-Animal PET", Journal of Nuclear Medicine, Vol. 48/6, https://doi.org/10.2967/jnumed.106.038539. 

Krukowski, K. et al. (2018a), "Female mice are protected from space radiation-induced maladaptive responses", Brain, Behavior, and Immunity, Vol. 74, Academic Press Inc., https://doi.org/10.1016/j.bbi.2018.08.008. 

Krukowski, K. et al. (2018b), "Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits", Scientific Reports 2018 8:1, Vol. 8/1, Nature Publishing Group, https://doi.org/10.1038/s41598-018-26039-7. 

Kyrkanides, S. et al. (1999), "TNFα and IL-1β mediate intercellular adhesion molecule-1 induction via microglia-astrocyte interaction in CNS radiation injury", Journal of Neuroimmunology, Vol. 95/1–2, Elsevier, Amsterdam, https://doi.org/10.1016/S0165-5728(98)00270-7. 

Langston, P. K., M. Shibata and T. Horng. (2017), "Metabolism Supports Macrophage Activation", Frontiers in Immunology, Vol. 8, Frontiers, https://doi.org/10.3389/fimmu.2017.00061. 

Makale, M. T. et al. (2017), "Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours", Nature Reviews Neurology, Vol. 13/1, Nature, https://doi.org/10.1038/nrneurol.2016.185. 

Mavragani, I. V. et al. (2016), "Key mechanisms involved in ionizing radiation-induced systemic effects. A current review", Toxicology Research, Vol. 5/1, Oxford University Press, Oxford, https://doi.org/10.1039/c5tx00222b. 

McCollough, C. H. et al. (2007), "Radiation Exposure and Pregnancy: When Should We Be Concerned?", RadioGraphics, Vol. 27/4, Radiological Society of North America, Oak Brook, https://doi.org/10.1148/rg.274065149. 

Mizumatsu, S. et al. (2003), "Extreme sensitivity of adult neurogenesis to low doses of X-irradiation", Cancer Research, Vol. 63/14. 

Moldoveanu, B. et al. (2009), "Inflammatory mechanisms in the lung.", Journal of inflammation research, Vol. 2, pp. 4021–4027, American Association for Cancer Research. 

Monje, M. L. et al. (2002), "Irradiation induces neural precursor-cell dysfunction", Nature Medicine, Vol. 8/9, Nature, https://doi.org/10.1038/nm749. 

Moravan, M. J. et al. (2011), "Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain", Radiation Research, Vol. 176/4, BioOne, https://doi.org/10.1667/RR2587.1. 

Multhoff, G. and J. Radons. (2012), "Radiation, Inflammation, and Immune Responses in Cancer", Frontiers in Oncology, Vol. 2, Frontiers, https://doi.org/10.3389/fonc.2012.00058. 

Niemantsverdriet, M. et al. (2012), "High and Low LET Radiation Differentially Induce Normal Tissue Damage Signals", International Journal of Radiation Oncology*Biology*Physics, Vol. 83/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijrobp.2011.09.057. 

Paladini, M. S. et al. (2021), "Microglia depletion and cognitive functions after brain injury: From trauma to galactic cosmic ray", Neuroscience Letters, Vol. 741, Elsevier, Amsterdam, https://doi.org/10.1016/j.neulet.2020.135462. 

Parihar, V. K. et al. (2016), "Cosmic radiation exposure and persistent cognitive dysfunction", Scientific Reports, Vol. 6/June, Nature Publishing Group, https://doi.org/10.1038/srep34774. 

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, Academic Press Inc., https://doi.org/10.1016/j.expneurol.2018.03.009. 

Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in behavioral neuroscience, Vol. 14, Frontiers, https://doi.org/10.3389/fnbeh.2020.535885. 

Patel, R. et al. (2020), "Protons and High-Linear Energy Transfer Radiation Induce Genetically Similar Lymphomas With High Penetrance in a Mouse Model of the Aging Human Hematopoietic System.", International journal of radiation oncology*biology*physics, Vol. 108/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijrobp.2020.06.070. 

Pinto, A. et al. (2016), "Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities", Scientific Reports, Vol. 6/1, Nature, https://doi.org/10.1038/srep18765. 

Poulose, S. M. et al. (2011), "Exposure to 16O-particle radiation causes aging-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy", Radiation Research, Vol. 176/6, BioOne, https://doi.org/10.1667/RR2605.1. 

Raber, J. et al. (2019), "Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice", Frontiers in physiology, Vol. 10, Frontiers, https://doi.org/10.3389/fphys.2019.00179. 

Rienecker, K. D. A. et al. (2021), "Microglia: Ally and Enemy in Deep Space", Neuroscience & Biobehavioral Reviews, Vol. 126, https://doi.org/10.1016/j.neubiorev.2021.03.036. 

Rodel, F. et al. (2012), "Modulation of Inflammatory Immune Reactions by Low-Dose Ionizing Radiation: Molecular Mechanisms and Clinical Application", Current Medicinal Chemistry, Vol. 19/12, Bentham Science Publishers, https://doi.org/10.2174/092986712800099866

Roh, J. S. and D. H. Sohn. (2018), "Damage-Associated Molecular Patterns in Inflammatory Diseases.", Immune network, Vol. 18/4, https://doi.org/10.4110/in.2018.18.e27. 

Rola, R. et al. (2008), "Hippocampal Neurogenesis and Neuroinflammation after Cranial Irradiation with 56 Fe Particles", Radiation Research, Vol. 169/6, BioOne, https://doi.org/10.1667/RR1263.1. 

Rola, R. et al. (2004), "Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice", Experimental Neurology, Vol. 188/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.expneurol.2004.05.005. 

Rola, R. et al. (2007), "Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis", Free radical biology & medicine, Vol. 42/8, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2007.01.020. 

Rowley, A. F. (1996), "The evolution of inflammatory mediators", Mediators of inflammation, Vol. 5/1, Hindawi, https://doi.org/10.1155/S0962935196000014. 

Schaue, D. et al. (2015), "Radiation and inflammation", Seminars in radiation oncology, Vol. 25/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.semradonc.2014.07.007

Sonetti, D. et al. (1994), "Microglia in invertebrate ganglia", Proceedings of the National Academy of Sciences of the United States of America, Vol. 91/19, National Academy of Science, https://doi.org/10.1073/pnas.91.19.9180. 

Suman, S. et al. (2013), "Therapeutic and space radiation exposure of mouse brain causes impaired dna repair response and premature senescence by chronic oxidant production", Aging, Vol. 5/8, https://doi.org/10.18632/aging.100587. 

Szabo, G., P. Mandrekar and A. Dolganiuc. (2007), "Innate immune response and hepatic inflammation", Seminars in liver disease, Vol. 27/4, Thieme, https://doi.org/10.1055/s-2007-991511. 

Vénéreau, E., C. Ceriotti and M. E. Bianchi. (2015), "DAMPs from Cell Death to New Life", Frontiers in immunology, Vol. 6, Frontiers, https://doi.org/10.3389/fimmu.2015.00422. 

Xu, P. et al. (2015), "Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor", Brain, Behavior, and Immunity, Vol. 50, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbi.2015.06.020. 

Yahyapour, R. et al. (2018), "Radiation-induced inflammation and autoimmune diseases", Military Medical Research, Vol. 5/1, Nature, https://doi.org/10.1186/s40779-018-0156-7. 

Zhao, W. and M. Robbins. (2009), "Inflammation and Chronic Oxidative Stress in Radiation-Induced Late Normal Tissue Injury: Therapeutic Implications", Current Medicinal Chemistry, Vol. 16/2, Bentham Science, https://doi.org/10.2174/092986709787002790.