Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain

Osman, Ahmed; Sun, Ying; Burns, Terry C.; He, Liqun; Kee, Nigel; Oliva‐Vilarnau, Nuria; Alevyzaki, Androniki; Zhou, Kai; Louhivuori, Lauri; Uhlén, Per; Hedlund, Eva; Betsholtz, Christer; Lauschke, Volker M.; Kele, Julianna; Blomgren, Klas

doi:10.1016/j.celrep.2020.107699

Cited by 35 publications

(37 citation statements)

References 94 publications

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“…Although the Warburg effect was first described in cancer cells, immune cells may also undergo glycolytic reprogramming [ 10 , 11 ]. Microglia cells, as resident macrophages, are triggered by irradiation [ 27 ]. Different degrees of dependance on glycolysis or oxidative phosphorylation lead to different degrees of polarization of microglia cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Monitoring Early Glycolytic Flux Alterations Following Radiotherapy in Cancer and Immune Cells: Hyperpolarized Carbon-13 Magnetic Resonance Imaging Study

Lai

Hsieh

et al. 2021

Metabolites

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Alterations in metabolism following radiotherapy affect therapeutic efficacy, although the mechanism underlying such alterations is unclear. A new imaging technique—named dynamic nuclear polarization (DNP) carbon-13 magnetic resonance imaging (MRI)—probes the glycolytic flux in a real-time, dynamic manner. The [1-13C]pyruvate is transported by the monocarboxylate transporter (MCT) into cells and converted into [1-13C]lactate by lactate dehydrogenase (LDH). To capture the early glycolytic alterations in the irradiated cancer and immune cells, we designed a preliminary DNP 13C-MRI study by using hyperpolarized [1-13C]pyruvate to study human FaDu squamous carcinoma cells, HMC3 microglial cells, and THP-1 monocytes before and after irradiation. The pyruvate-to-lactate conversion rate (kPL [Pyr.]) calculated by kinetic modeling was used to evaluate the metabolic alterations. Western blotting was performed to assess the expressions of LDHA, LDHB, MCT1, and MCT4 proteins. Following irradiation, the pyruvate-to-lactate conversion rates on DNP 13C-MRI were significantly decreased in the FaDu and the HMC3 cells but increased in the THP-1 cells. Western blot analysis confirmed the similar trends in LDHA and LDHB expression levels. In conclusion, DNP 13C-MRI non-invasively captured the different glycolytic alterations among cancer and immune systems in response to irradiation, implying its potential for clinical use in the future.

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Section: Discussionmentioning

confidence: 99%

Monitoring Early Glycolytic Flux Alterations Following Radiotherapy in Cancer and Immune Cells: Hyperpolarized Carbon-13 Magnetic Resonance Imaging Study

Lai

Hsieh

et al. 2021

Metabolites

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“…Cell and animal research continue to help bridge the gap in areas which human studies cannot explore. Various studies have shown a range of microglial responses to high dose ionising radiation; notably that irradiation using a high dosage will elicit a neuroinflammatory response [18,[114][115][116][117][118]. A dose of 0.5 Gy has been shown to increase the number of microglia in the hippocampus, compared to control and low dose ionising radiation (0.063 Gy); however, the microglia were less ramified than before [118].…”

Section: Impact Of Ionising Radiation On Healthy Brains By Altering Microglial Function Statesmentioning

confidence: 99%

“…Microglia, the resident immune cells of the central nervous system (CNS), respond to external stressors such as pathogenic invasion and injury by inducing inflammation [16][17][18]. During microglial activation, microglia are polarised from the M2 anti-inflammatory state to the M1 pro-inflammatory state [16,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Control of Neuroinflammation through Radiation-Induced Microglial Changes

Boyd

Byrne

Middleton

et al. 2021

Cells

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Microglia, the innate immune cells of the central nervous system, play a pivotal role in the modulation of neuroinflammation. Neuroinflammation has been implicated in many diseases of the CNS, including Alzheimer’s disease and Parkinson’s disease. It is well documented that microglial activation, initiated by a variety of stressors, can trigger a potentially destructive neuroinflammatory response via the release of pro-inflammatory molecules, and reactive oxygen and nitrogen species. However, the potential anti-inflammatory and neuroprotective effects that microglia are also thought to exhibit have been under-investigated. The application of ionising radiation at different doses and dose schedules may reveal novel methods for the control of microglial response to stressors, potentially highlighting avenues for treatment of neuroinflammation associated CNS disorders, such as Alzheimer’s disease and Parkinson’s disease. There remains a need to characterise the response of microglia to radiation, particularly low dose ionising radiation.

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“…Multiple progenitor cell populations are now known to reside in the adult human brain 34. Injury to the mammalian brain can trigger a tightly orchestrated, dynamic response that involves many cell types, including microglia, astrocytes, and endogenous neural progenitors 56. Genetic tools to inhibit innate responses may exacerbate the resultant damage 7.…”

Section: Introductionmentioning

confidence: 99%

Regenerative medicine for neurological diseases—will regenerative neurosurgery deliver?

Burns¹,

Quiñones‐Hinojosa

2021

BMJ

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Regenerative medicine aspires to transform the future practice of medicine by providing curative, rather than palliative, treatments. Healing the central nervous system (CNS) remains among regenerative medicine’s most highly prized but formidable challenges. “Regenerative neurosurgery” provides access to the CNS or its surrounding structures to preserve or restore neurological function. Pioneering efforts over the past three decades have introduced cells, neurotrophins, and genes with putative regenerative capacity into the CNS to combat neurodegenerative, ischemic, and traumatic diseases. In this review we critically evaluate the rationale, paradigms, and translational progress of regenerative neurosurgery, harnessing access to the CNS to protect, rejuvenate, or replace cell types otherwise irreversibly compromised by neurological disease. We discuss the evidence surrounding fetal, somatic, and pluripotent stem cell derived implants to replace endogenous neuronal and glial cell types and provide trophic support. Neurotrophin based strategies via infusions and gene therapy highlight the motivation to preserve neuronal circuits, the complex fidelity of which cannot be readily recreated. We specifically highlight ongoing translational efforts in Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and spinal cord injury, using these to illustrate the principles, challenges, and opportunities of regenerative neurosurgery. Risks of associated procedures and novel neurosurgical trials are discussed, together with the ethical challenges they pose. After decades of efforts to develop and refine necessary tools and methodologies, regenerative neurosurgery is well positioned to advance treatments for refractory neurological diseases. Strategic multidisciplinary efforts will be critical to harness complementary technologies and maximize mechanistic feedback, accelerating iterative progress toward cures for neurological diseases.

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Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain

Cited by 35 publications

References 94 publications

Monitoring Early Glycolytic Flux Alterations Following Radiotherapy in Cancer and Immune Cells: Hyperpolarized Carbon-13 Magnetic Resonance Imaging Study

Monitoring Early Glycolytic Flux Alterations Following Radiotherapy in Cancer and Immune Cells: Hyperpolarized Carbon-13 Magnetic Resonance Imaging Study

Control of Neuroinflammation through Radiation-Induced Microglial Changes

Regenerative medicine for neurological diseases—will regenerative neurosurgery deliver?

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