Microglia as Therapeutic Target for Radiation-Induced Brain Injury
Abstract
:1. Introduction
2. Overview of Microglia Physiological Functions
3. Microglia in Radiation-Induced Brain Injury
3.1. Microglial Activation
3.2. ROS/RNS Production and Oxidative Stress
3.3. Regulation of BBB Integrity
3.4. Immune Cell Infiltration in the Brain
4. Modulation of Microglia for RIBI Therapy
4.1. Colony Stimulating Factor 1 Receptor (CSF1R)
4.2. Complement Receptors and Complement Components
4.3. Purinergic Receptors
4.4. CX3CR1
4.5. Peroxisome Proliferator-Activated Receptors (PPARs)
4.6. Kv1.3 Channel
4.7. MicroRNAs (miRNAs)
4.8. Long Non-Coding RNAs (lncRNAs)
4.9. Extracellular Vesicles (EVs)
Targets | Animal/Cell Model | Source Dose and Dose Rate | Irradiated Site | Time Point after Radiation | Intervention Effect in Irradiation Models | Reference |
---|---|---|---|---|---|---|
CSFR1 | C57BL/6J mouse | X-ray with 9 cGy (1.10 Gy/min) | whole brain | 3 days, 2 weeks, 6 weeks | CSFR1 inhibition reduces the increase in mRNA of inflammation markers (TLR9, SYK, CCL6, CD14, CLECL5a, TSLP, CCL5) and the number of activated microglia in hippocampus and ameliorates cognitive dysfunction. | [141] |
4He particles with 30 cGy (15–25 cGy/min) | 4–6 weeks | CSFR1 inhibition ameliorates cognitive dysfunction, reduces activated microglia population, and attenuates the increase in PSD-95 puncta but does not affect morphologic and electrophysiologic features of neurons. | [143] | |||
4He particles with 15 cGy (16.37 cGy/min) 50 cGy (16.95 cGy/min) 100 cGy (18.07 cGy/min) | 18–21 days and 90–100 days | CSFR1 inhibition improves long-term cognitive impairment and inflammatory response, decreases C5aR and LAMP-1, and increases synapsin-1. | [144] | |||
γ ray with three fractions of 3.3 Gy | 1, 3 months | CSFR1 blockade reduces the numbers of activated microglia, suppresses monocyte accumulation in brain, and ameliorates cognitive dysfunction. | [142] | |||
C1q | C57BL/6 mouse | γ-ray with 9 Gy (1.2 Gy/min) | whole brain | 2, 24, 48 h; 1, 2, 3, 4 weeks | Deletion of C1q in microglia protects synaptic loss and reduces activation of microglia and astrocytes, as well as protein levels of TNF-a, IL-1ß, IL-6, IL-1α, CCL2, IL-18, and TLR4. | [71] |
C3 | C57BL/6 mouse | X-ray with 8 Gy (2.3 Gy/min) | whole brain | 6 h; 7 days; 2, 3, 4 weeks | C3 knockout improves task performance and increases activated microglia and proliferating cells in the granule cell layer. | [165] |
C3R | C57BL/6J mouse | γ-ray with 10 Gy (1.17 Gy/min) | whole brain | 30 days | CR3 blockade ameliorates behavior deficits in novel object recognition and the Lashley III maze, prevents dendritic spine loss, and increases CD11-positive microglia in hippocampus. | [166] |
30, 45 days | CR3 knockout prevents dendritic spine loss and increases activated microglia in hippocampus. | [145] | ||||
P2Y6 | Balb/c mouse | β-ray with 30 Gy (3 Gy/min) | whole brain | 1, 14, 30 days | P2Y6 receptor antagonism suppresses phagocytosis of irradiated microglia and increases the number of apoptotic neurons. | [182] |
Primary microglia | β-ray with 8 Gy | 4, 12, 48 h | P2Y6 receptor antagonism suppresses phagocytosis of irradiated microglia and has no effect on the production of inflammatory mediators (TNF-α, IL-1β, IL-6, iNOS). | [182] | ||
P2X7 | Balb/c mouse | β-ray with 30 Gy (3 Gy/min) | whole brain | 3, 7, 14 days; 8 weeks | P2X7R blockade reduces the activated microglia population and neuron loss in the cortex. | [69] |
Primary microglia | β-ray with 10 Gy (6 MeV/min) | 24, 48 h | P2X7R blockade reduces the activated microglia population and mRNA expression levels of IL-6, TNF-α, and COX-2. | [69] | ||
CX3CR1 | C57BL/6J mouse | γ-ray with 10 Gy (2 Gy/min) | whole brain | 3, 6, 12, 24, 48, 72 h; 1, 2, 4 weeks | FKN overexpression promotes M2 phenotypic polarization, reverses the reduced neural stem cell in hippocampus, decreases the TNF-α level, and increases the IL-10 level in the blood. | [20] |
BV-2 | γ-ray with 10 Gy (2.0 Gy/min) | 1.5, 6 h | FKN promotes microglial phagocytosis and M2 polarization, decreases TNF-α and IL-1β mRNA levels, and increases IL-10 mRNA levels. CX3CR1 knockdown reverses these effects. | [20] | ||
PPARα | BV-2 | γ-ray with 10 Gy (4.0 Gy/min) | 1, 3, 7, 12, 24 h | PPARα activation prevents the increase in IL-1, and TNF-α mRNA levels, and COX-2 protein via inhibition of p65 translocation and jun phosphorylation. | [83] | |
129S1/SvImJ mouse | γ-ray with 10 Gy (3.33 Gy/min) | whole brain | 1 week, 2 months | PPARα activation promotes newborn neuron survival and prevents microglial activation. PPARα knockout abolishes the neuroprotection of fenofibrate. | [201] | |
Fischer 344 × Brown Norway rats | γ-ray with four fractions of 10 Gy (4 Gy/min) | whole brain | 26, 29 weeks | PPARα activation prevents perirhinal cortex-dependent cognitive impairment without a decrease in microglial activation and an increase in immature neurons. | [78] | |
PPARδ | BV-2 | γ-ray with 10 Gy (3.56 Gy/min) | 30 min; 7, 24 h | PPARδ activation downregulates ROS production, IL-1 and TNF-α expression, and COX-2 and MCP-1 proteins by inhibiting NF-κB and PKCα/MEK1/2/ERK1/2/AP pathways. | [18] | |
C57BL/6J | γ-ray with 10 Gy (5 Gy/min) | whole brain | 3 h; 1, 2 weeks | PPARδ activation prevents the increase in IL-1 gene expression and pERK protein but does not rescue neurogenesis and hippocampal-dependent cognitive impairment. | [203] | |
PPARγ | Fischer 344 rat | γ-ray with nine fractions of 5 Gy (4.41 Gy/min) | whole brain | 50, 54 weeks | PPARγ activation prevents cognitive impairment. | [206] |
Kv 1.3 | Balb/c mouse | ß-ray with 30 Gy (3 Gy/min) | whole brain | 3, 14 days; 8 weeks | Kv 1.3 blockade prevents neuronal loss and increases activated microglial in hippocampus and cerebral cortex and improves spatial learning and cerebral cortex atrophy in mice. | [74] |
BV-2 | ß-ray with 10 Gy (3 Gy/min) | 4, 12 h; 1, 2 days | Kv 1.3 blockade or knockdown decreases protein and mRNA level of TNF-α, IL-6, and COX-2 in microglia and inhibits apoptosis of co-cultured primary hippocampal neurons. | [74] | ||
miR-124 | C57BL/6J mouse | γ-ray with 10 Gy (2.07 Gy/min) | whole brain | 5 weeks | miR-124 overexpression prevents microglia activation and ameliorates cognitive impairment. | [231] |
miR-741-3p | C57BL/6J mouse | ß-ray with 30 Gy (2.5 Gy/min) | whole brain | 1, 6 weeks | miR-741-3p inhibition resists cognitive dysfunction, hippocampal neuronal injury, and microglia activation and decreases the expression level of IL-6 and TNF-a. | [229] |
miR-122-5p | C57BL/6J mouse | ß-ray with 30 Gy (3 Gy/min) | whole brain | 6 weeks, 48–50 days | miR-122-5p inhibition prevents cognitive impairment, neuronal damage, microglia activation, and production of TNF-a, IL-6, and IL-1ß in hippocampus. | [230] |
BV-2 | ß-ray with 10 Gy | 8, 24 h | miR-122-5p inhibition alleviates the decrease in cell viability and increase in the release of TNF-a, IL-6, and IL-1ß in BV2; restores BV2 branching morphogenesis and phagocytosis; and reduces co-cultured SH-SY5Y cell apoptosis. | [230] | ||
lncRNA ENSMUST00000130679 | BV-2 | X-ray with 10 Gy (2 Gy/min) | 1, 24 h | lncRNA ENSMUST00000130679 knockdown suppresses DDR; phosphorylation of p65, JNK, and p38; and release of TNF-a, IL-6, and IL-1ß in BV2. | [66] | |
lncRNA ENSMUST00000190863 | BV-2 | X-ray with 10 Gy (2 Gy/min) | 1, 24 h | lncRNA ENSMUST00000190863 knockdown suppresses DDR, phosphorylation of p65, and release of TNF-a in BV2. | [66] | |
hNSC-derived MV | athymic nude rats | X-ray with 10 Gy (1 Gy/min) | whole brain | 4–7 weeks | MV transplantation into the bilateral hippocampus reduces the number of activated microglia in the hippocampus, neocortex (layer II/III), and amygdala; recovers the complexity of neuronal architecture; and ameliorates cognitive impairment. | [244] |
1 month | MV transplantation into the unilateral hippocampus reduces the number of activated microglia in the ipsilateral hippocampus; bilateral or unilateral transplantation increases GDNF and restores PSD-95 protein level in bilateral hippocampus; neither bilateral nor unilateral transplantation protects dendritic spine density. | [243] | ||||
hNSC-derived EV | C57BL/6J mouse | γ-ray with 10 Gy (2.07 Gy/minute) | whole brain | 5 weeks, 6 months | EV transplantation into the bilateral hippocampus prevents microglia activation in the hippocampus and ameliorates cognitive impairment. | [231] |
ADMSC-Exos | Sprague–Dawley rats | γ-ray with 30 Gy (1.59 Gy/min) | whole brain | 24 h; 3, 7 days | Tail vein injection pf ADMSC-Exos decreases the levels of caspase-3, MDA, 8-OHdG, TNF-α, IL-4, and SIRT1 and promotes recovery of SOD, CAT, IL-4, and IL-10 levels and suppresses microglial infiltration. | [73] |
primary microglia | γ-ray with 30 Gy (3 MeV/min) | 24 h | Tail vein injection of ADMSC-Exos decreases the levels of caspase-3, MDA, 8-OHdG, TNF-α, IL-4, and SIRT1 and promotes the recovery of SOD, CAT, IL-4, and IL-10 levels and suppresses microglial activation. The above effects of ADMSC-Exos are inhibited by the SIRT-1 inhibitor EX527. | [73] |
5. Conclusions and Open Questions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Liu, Q.; Huang, Y.; Duan, M.; Yang, Q.; Ren, B.; Tang, F. Microglia as Therapeutic Target for Radiation-Induced Brain Injury. Int. J. Mol. Sci. 2022, 23, 8286. https://doi.org/10.3390/ijms23158286
Liu Q, Huang Y, Duan M, Yang Q, Ren B, Tang F. Microglia as Therapeutic Target for Radiation-Induced Brain Injury. International Journal of Molecular Sciences. 2022; 23(15):8286. https://doi.org/10.3390/ijms23158286
Chicago/Turabian StyleLiu, Qun, Yan Huang, Mengyun Duan, Qun Yang, Boxu Ren, and Fengru Tang. 2022. "Microglia as Therapeutic Target for Radiation-Induced Brain Injury" International Journal of Molecular Sciences 23, no. 15: 8286. https://doi.org/10.3390/ijms23158286