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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
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Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated

Guoku Hu1, Ke Liao1, Fang Niu1

  • 1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.

Molecular Therapy. Nucleic Acids
|November 3, 2018
PubMed

Insights

Morphine-induced astrocyte extracellular vesicles impair microglial phagocytosis by upregulating long intergenic noncoding RNA-Cox2. Intranasal delivery of these vesicles with siRNA restored microglial function, suggesting a therapeutic approach for neurodegenerative disorders.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Microglial dysfunction is implicated in neurodegenerative diseases.
  • Long intergenic noncoding RNA-Cox2 (lincRNA-Cox2) is regulated by NF-κB signaling and affects immune gene expression in microglia.
  • Extracellular vesicles (EVs) mediate intercellular communication.

Purpose of the Study:

  • To investigate the role of astrocyte-derived EVs in morphine-induced microglial impairment.
  • To explore the mechanism involving lincRNA-Cox2 and Toll-like receptor 7 (TLR7).
  • To evaluate the therapeutic potential of EV-based RNA delivery.

Main Methods:

  • Treatment of astrocytes with morphine and collection of EVs.
  • Uptake of EVs by microglia and analysis of lincRNA-Cox2 expression and TLR7 activation.
  • Assessment of microglial phagocytosis in vitro and in vivo using brain slices from morphine-administered mice.
  • Intranasal delivery of EVs containing lincRNA-Cox2 siRNA in mice.

Main Results:

  • Astrocytes exposed to morphine released EVs that, upon uptake by microglia, activated TLR7 and upregulated lincRNA-Cox2.
  • This resulted in impaired microglial phagocytosis, confirmed in vivo.
  • Intranasal administration of EVs carrying lincRNA-Cox2 siRNA restored microglial phagocytic activity in morphine-treated mice.

Conclusions:

  • Astrocyte-derived EVs play a critical role in morphine-induced microglial dysfunction.
  • The mechanism involves TLR7 activation and subsequent lincRNA-Cox2 upregulation, leading to impaired phagocytosis.
  • EV-encapsulated RNA therapeutics offer a promising strategy for treating disorders characterized by microglial impairment.
Keywords:
CNSdrug abuseexosomeextracellular vesiclelincRNAmicrogliamorphinephagocytosis

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