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Abscopal Activation of Microglia in Embryonic Fish Brain Following Targeted Irradiation with Heavy-Ion Microbeam.

ABSTRACT: Microglia remove apoptotic cells by phagocytosis when the central nervous system is injured in vertebrates. Ionizing irradiation (IR) induces apoptosis and microglial activation in embryonic midbrain of medaka (Oryzias latipes), where apolipoprotein E (ApoE) is upregulated in the later phase of activation of microglia In this study, we found that another microglial marker, l-plastin (lymphocyte cytosolic protein 1), was upregulated at the initial phase of the IR-induced phagocytosis when activated microglia changed their morphology and increased motility to migrate. We further conducted targeted irradiation to the embryonic midbrain using a collimated microbeam of carbon ions (250 μm diameter) and found that the l-plastin upregulation was induced only in the microglia located in the irradiated area. Then, the activated microglia might migrate outside of the irradiated area and spread through over the embryonic brain, expressing ApoE and with activated morphology, for longer than 3 days after the irradiation. These findings suggest that l-plastin and ApoE can be the biomarkers of the activated microglia in the initial and later phase, respectively, in the medaka embryonic brain and that the abscopal and persisted activation of microglia by IR irradiation could be a cause of the abscopal and/or adverse effects following irradiation.

SUBMITTER: Yasuda T

PROVIDER: S-EPMC5535919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin environment by different high-resolution microscopy approaches. Using the heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at 0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). Increasing numbers of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner. In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over the first hours following IR exposure, indicating the challenging task for the cell to process highly clustered DSBs appropriately. Increasing numbers of carbon ions applied to sub-nuclear chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment.

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Abscopal Activation of Microglia in Embryonic Fish Brain Following Targeted Irradiation with Heavy-Ion Microbeam.

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