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

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages450-463
Number of pages14
JournalMolecular Therapy - Nucleic Acids
Volume13
DOIs
StatePublished - Dec 7 2018

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Long Noncoding RNA
Phagocytosis
Astrocytes
Morphine
Microglia
Toll-Like Receptor 7
Endosomes
Cell Communication
Neurodegenerative Diseases
Small Interfering RNA
Up-Regulation
RNA
Extracellular Vesicles
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis : Implications for Morphine-Mediated Neurodegeneration. / Hu, Guoku; Liao, Ke; Niu, Fang; Yang, Lu; Dallon, Blake W.; Callen, Shannon; Tian, Changhai; Shu, Jiang; Cui, Juan; Sun, Zhiqiang; Lyubchenko, Yuri L.; Ka, Minhan; Chen, Xian-Ming; Buch, Shilpa.

In: Molecular Therapy - Nucleic Acids, Vol. 13, 07.12.2018, p. 450-463.

Research output: Contribution to journalArticle

Hu, G, Liao, K, Niu, F, Yang, L, Dallon, BW, Callen, S, Tian, C, Shu, J, Cui, J, Sun, Z, Lyubchenko, YL, 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, vol. 13, pp. 450-463. https://doi.org/10.1016/j.omtn.2018.09.019
Hu, Guoku ; Liao, Ke ; Niu, Fang ; Yang, Lu ; Dallon, Blake W. ; Callen, Shannon ; Tian, Changhai ; Shu, Jiang ; Cui, Juan ; Sun, Zhiqiang ; Lyubchenko, Yuri L. ; Ka, Minhan ; Chen, Xian-Ming ; Buch, Shilpa. / Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis : Implications for Morphine-Mediated Neurodegeneration. In: Molecular Therapy - Nucleic Acids. 2018 ; Vol. 13. pp. 450-463.
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