Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration

Guoku Hu, Ke Liao, Fang Niu, Lu Yang, Blake W. Dallon, Shannon Callen, Changhai Tian, Jiang Shu, Juan Cui, Zhiqiang Sun, Yuri L. Lyubchenko, Minhan Ka, Xian Ming Chen, Shilpa Buch

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21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)450-463
Number of pages14
JournalMolecular Therapy - Nucleic Acids
Volume13
DOIs
StatePublished - Dec 7 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Hu, G., Liao, K., Niu, F., Yang, L., Dallon, B. W., Callen, S., Tian, C., Shu, J., Cui, J., Sun, Z., Lyubchenko, Y. L., Ka, M., Chen, X. M., & Buch, S. (2018). Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration. Molecular Therapy - Nucleic Acids, 13, 450-463. https://doi.org/10.1016/j.omtn.2018.09.019