Abstract
It is known that cerebral ischemia can cause brain inflammation and adiposome can serve as a depot of inflammatory mediators. In the study, the pro-inflammatory and pro-death role of adiposome in ischemic microglia and ischemic brain was newly investigated. The contribution of PPARγ to adiposome formation was also evaluated for the first time in ischemic microglia. Focal cerebral ischemia/reperfusion (I/R) animal model and the in vitro glucose-oxygen-serum deprivation (GOSD) cell model were both applied in the study. GOSD- or I/R-induced adiposome formation, inflammatory activity, cell death of microglia, and brain infarction were, respectively, determined, in the absence or presence of NS-398 (adiposome inhibitor) or GW9662 (PPARγ antagonist). GOSD-increased adiposome formation played a critical role in stimulating the inflammatory activity (production of TNF-α and IL-1β) and cell death of microglia. Similar results were also found in ischemic brain tissues. GOSD-induced PPARγ partially contributed to the increase of adiposomes and adiposome-mediated inflammatory responses of microglia. Blockade of adiposome formation with NS-398 or GW9662 significantly reduced not only the inflammatory activity and death rate of GOSD-treated microglia but also the brain infarct volume and motor function deficit of ischemic rats. The pathological role of microglia-derived adiposome in cerebral ischemia has been confirmed and attributed to its pro-inflammatory and/or pro-death effect upon ischemic brain cells and tissues. Adiposome and its upstream regulator PPARγ were therefore as potential targets for the treatment of ischemic stroke. Therapeutic values of NS-398 and GW9662 have been suggested.
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Acknowledgements
This study was financially supported by Grants MOST103-2320-B-005-001, TCVGH-NCHU1027613, MacKay Memorial Hospital Grant MMH-102-46, and the iEGG and Animal Biotechnology Center from The Feature Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.
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CHL analyzed the data and wrote the paper; LYL designed and executed most of the experiments and analyzed the data; YJC performed the experiments in Figs. 4d and 2d; CWT performed the experiments in Figs. 4e and 5d; TYY and SLH supported the work and edited the paper; CMH conceived the project, designed experiments, supervised others, and edited the manuscript.
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Lin, CH., Liao, LY., Yang, TY. et al. Microglia-Derived Adiposomes are Potential Targets for the Treatment of Ischemic Stroke. Cell Mol Neurobiol 39, 591–604 (2019). https://doi.org/10.1007/s10571-019-00665-9
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DOI: https://doi.org/10.1007/s10571-019-00665-9