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 κB (NF-κB) 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.
|Number of pages||14|
|Journal||Molecular Therapy - Nucleic Acids|
|State||Published - Dec 7 2018|
Bibliographical noteFunding Information:
This work was supported by grants DA041751, DA043164, MH112848, DA040397, DA043138 (to S.B.), and DA042704 and DA046831 (to G.H.) from the NIH . The support of the Nebraska Center for Substance Abuse Research is acknowledged. The project described was also supported by the NIH , National Institute of Mental Health (grant 2P30MH062261 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
© 2018 The Authors
- drug abuse
- extracellular vesicle
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery