Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 13, Issue -, Pages 450-463Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2018.09.019
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Funding
- NIH [DA041751, DA043164, MH112848, DA040397, DA043138, DA042704, DA046831]
- Nebraska Center for Substance Abuse Research
- NIH, National Institute of Mental Health [2P30MH062261]
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH112848, P30MH062261] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA041751, R01DA043138, R01DA043164, R01DA040397, R21DA046831, R21DA042704] Funding Source: NIH RePORTER
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Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor kappa B (NF-kappa B) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation. Herein, we show that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) with a subsequent upregulation of lincRNA-Cox2 expression, ultimately resulting in impaired microglial phagocytosis. This was further validated in vivo, wherein inhibition of microglial phagocytic activity was also observed in brain slices isolated from morphine-administrated mice compared with control mice. Additionally, we also showed that intranasal delivery of EVs containing lincRNA-Cox2 siRNA (small interfering RNA) was able to restore microglial phagocytic activity in mice administered morphine. These findings have ramifications for the development of EV-loaded RNA-based therapeutics for the treatment of various disorders involving functional impairment of microglia.
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