Spencer, NG; Schilling, T; Miralles, F; Eder, C
(2016)
Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.
PLoS One, 11 (9).
ISSN 1932-6203
https://doi.org/10.1371/journal.pone.0162497
SGUL Authors: Eder, Claudia Miralles Arenas, Francisco Schilling, Tom
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Abstract
Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology.
Item Type: | Article | ||||||
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Additional Information: | © 2016 Spencer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||||||
Keywords: | General Science & Technology, MD Multidisciplinary | ||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) Academic Structure > Institute of Medical & Biomedical Education (IMBE) Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE) |
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Journal or Publication Title: | PLoS One | ||||||
Article Number: | e0162497 | ||||||
ISSN: | 1932-6203 | ||||||
Language: | eng | ||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||
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PubMed ID: | 27598576 | ||||||
Go to PubMed abstract | |||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/108266 | ||||||
Publisher's version: | https://doi.org/10.1371/journal.pone.0162497 |
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