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Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation
Ke Liao1, Fang Niu1, Guoku Hu1
1Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center Omaha Nebraska USA.
Abstract:
Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7-/- mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.
Insights
Morphine exposure triggers the release of miR-138 within extracellular vesicles (EVs), activating microglia via toll-like receptor 7 (TLR7). This mechanism drives neuroinflammation in opioid abuse, suggesting EV-based anti-miRNA therapies.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Opioids are crucial for pain management but associated with increased overdose deaths.
- Opioid abuse leads to neuroinflammation, though underlying mechanisms are not fully understood.
- MicroRNAs (miRNAs) are key regulators of gene expression and intercellular communication.
Purpose of the Study:
- To elucidate the mechanisms by which morphine induces neuroinflammation.
- To investigate the role of microRNAs and extracellular vesicles in morphine-induced neuroinflammation.
Main Methods:
- Primary human astrocytes were exposed to morphine.
- Extracellular vesicles (EVs) containing miRNAs were isolated from astrocyte-conditioned media.
- Microglia activation was assessed following EV uptake, with specific attention to toll-like receptor 7 (TLR7) interactions.
- In vivo studies utilized wildtype and TLR7 knockout mice.
Main Results:
- Morphine induced the release of miR-138 within EVs from astrocytes.
- These EVs were taken up by microglia, leading to their activation.
- Microglial activation was dependent on the binding of miR-138's GUUGUGU motif to TLR7.
- Morphine administration increased microglial activation in wildtype mice but not in TLR7 knockout mice.
Conclusions:
- Morphine-induced neuroinflammation involves miR-138 packaged in EVs, which activate microglia through TLR7.
- This pathway is critical for understanding opioid neurotoxicity.
- EV-loaded anti-miRNAs represent a potential therapeutic strategy for opioid-associated neuroinflammation.
