Control of Neuroinflammation through Radiation-Induced Microglial Changes

Boyd, Alexandra; Byrne, Sarah; Middleton, Ryan J.; Bánati, Richard B.; Liu, Guo Jun

doi:10.3390/cells10092381

Cited by 35 publications

(27 citation statements)

References 212 publications

(282 reference statements)

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“…Another study showed that application of low dose irradiation strengthens immunity and improves neurodegeneration in the animal models by altering the microglial phenotypes (reviewed by Boyd et al, 2021). Administration of low dose irradiation in microglia reduces microglial activation and enhances anti‐inflammatory cytokine and anti‐oxidant properties, thus enhancing neuroprotection (Boyd et al, 2021). This irradiation strategy to examine the mechanisms underlying the regulation of myelination by microglia remains untested in the CPZ model.…”

Section: Roles Of Astrocytes In Myelin Debris Clearancementioning

confidence: 99%

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

Sen

Mahns

Coorssen

et al. 2022

Glia

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In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up‐regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia‐mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.

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Section: Roles Of Astrocytes In Myelin Debris Clearancementioning

confidence: 99%

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

Sen

Mahns

Coorssen

et al. 2022

Glia

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“…LDIR may decrease systemic IL-6 levels in mice, including in the brain, through its direct effects on the cells that release cytokines, and indirectly through a reduction of TSPO. It has been demonstrated that the level of TSPO expression positively correlates to the concentration of pro-inflammatory cytokines, including IL-6 ( Karlstetter et al, 2014 ; Betlazar et al, 2016 , 2020 ; Boyd et al, 2021 ). Reversely, increased pro-inflammatory cytokines may trigger an elevated level of TSPO expression.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, given the link between the widespread constitutive TSPO expression in these cells, their ability to induce inflammatory responses and oxidative processes after irradiation, and the known involvement of TSPO in these processes, further studies are needed in order to gain insights into TSPO expression in this cell type after irradiation and its potential involvement in radiation-induced endothelial processes. It has been demonstrated that level of TSPO positively correlates with ROS production ( Gatliff et al, 2014 ; Betlazar et al, 2016 , 2020 ; Tu et al, 2016 ; Ilkan and Akar, 2018 ; Boyd et al, 2021 ). ROS and RNS can reversibly modulate TSPO expression ( Loth et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Translocator Protein (TSPO) Expression in the Brain After Whole Body Gamma Irradiation

Betlazar

Middleton

Howell

et al. 2021

Front. Cell Dev. Biol.

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The brain’s early response to low dose ionizing radiation, as may be encountered during diagnostic procedures and space exploration, is not yet fully characterized. In the brain parenchyma, the mitochondrial translocator protein (TSPO) is constitutively expressed at low levels by endothelial cells, and can therefore be used to assess the integrity of the brain’s vasculature. At the same time, the inducible expression of TSPO in activated microglia, the brain’s intrinsic immune cells, is a regularly observed early indicator of subtle or incipient brain pathology. Here, we explored the use of TSPO as a biomarker of brain tissue injury following whole body irradiation. Post-radiation responses were measured in C57BL/6 wild type (Tspo+/+) and TSPO knockout (Tspo–/–) mice 48 h after single whole body gamma irradiations with low doses 0, 0.01, and 0.1 Gy and a high dose of 2 Gy. Additionally, post-radiation responses of primary microglial cell cultures were measured at 1, 4, 24, and 48 h at an irradiation dose range of 0 Gy-2 Gy. TSPO mRNA and protein expression in the brain showed a decreased trend after 0.01 Gy relative to sham-irradiated controls, but remained unchanged after higher doses. Immunohistochemistry confirmed subtle decreases in TSPO expression after 0.01 Gy in vascular endothelial cells of the hippocampal region and in ependymal cells, with no detectable changes following higher doses. Cytokine concentrations in plasma after whole body irradiation showed differential changes in IL-6 and IL-10 with some variations between Tspo–/– and Tspo+/+ animals. The in vitro measurements of TSPO in primary microglial cell cultures showed a significant reduction 1 h after low dose irradiation (0.01 Gy). In summary, acute low and high doses of gamma irradiation up to 2 Gy reduced TSPO expression in the brain’s vascular compartment without de novo induction of TSPO expression in parenchymal microglia, while TSPO expression in directly irradiated, isolated, and thus highly activated microglia, too, was reduced after low dose irradiation. The potential link between TSPO, its role in mitochondrial energy metabolism and the selective radiation sensitivity, notably of cells with constitutive TSPO expression such as vascular endothelial cells, merits further exploration.

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“…There have been several studies using NSC/induced pluripotent stem cells (iPSCs) derived from Alzheimer patients with the objective of promoting neurogenesis and ameliorating the progression of the disease ( Wu et al, 2021 ). In one of these studies, for example, they demonstrate that the release of pro-inflammatory cytokines, such as TNF- α, IL-1 β, and IGF-1 by microglia enhance the dopaminergic differentiation of neural stem cells and promote neurogenesis ( Boyd et al, 2021 ; Schmidt et al, 2021 ).…”

Section: Effect Of Microglia On Neural Stem Cell Differentiation In A...mentioning

confidence: 99%

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Revuelta

Urrutia

Villarroel

et al. 2022

Front. Cell. Neurosci.

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Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer’s Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

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Control of Neuroinflammation through Radiation-Induced Microglial Changes

Cited by 35 publications

References 212 publications

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

Mitochondrial Translocator Protein (TSPO) Expression in the Brain After Whole Body Gamma Irradiation

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

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