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 language | English (US) |
|---|---|
| Pages (from-to) | 450-463 |
| Number of pages | 14 |
| Journal | Molecular Therapy - Nucleic Acids |
| Volume | 13 |
| DOIs | |
| State | Published - Dec 7 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis
T2 - Molecular Therapy - Nucleic Acids
AU - Hu, Guoku
AU - Liao, Ke
AU - Niu, Fang
AU - Yang, Lu
AU - Dallon, Blake W.
AU - Callen, Shannon
AU - Tian, Changhai
AU - Shu, Jiang
AU - Cui, Juan
AU - Sun, Zhiqiang
AU - Lyubchenko, Yuri L.
AU - Ka, Minhan
AU - Chen, Xian-Ming
AU - Buch, Shilpa
PY - 2018/12/7
Y1 - 2018/12/7
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85055331776&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2018.09.019
DO - 10.1016/j.omtn.2018.09.019
M3 - Article
VL - 13
SP - 450
EP - 463
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
SN - 2162-2531
ER -