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miR-124/VAMP3 is a novel therapeutic target for mitigation of surgical trauma-induced microglial activation

Chen, Yan, Sun, Jing-xian, Chen, Wan-kun, Wu, Gen-cheng, Wang, Yan-qing, Zhu, Ke-ying, Wang, Jun·2019·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-019-0061-xPMC PMC6799846
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Abstract

Activation of microglia and the subsequently elevated inflammatory cytokine release in the brain during surgery predispose individuals to cognitive dysfunction, also known as postoperative cognitive dysfunction (POCD). miR-124 is one of the most abundant microRNAs in the brain that regulates microglial function. Elucidating the role of miR-124 in microglial activation in the context of surgery may therefore promote understanding of as well as therapeutic development for post-surgical disorders involving microglial activation. The downstream targets of miR-124 were investigated using bioinformatic screening and dual-luciferase reporter assay validation, and vesicle-associated membrane protein 3 (VAMP3) was identified as a potential target. The kinetics of miR-124/VAMP3 expression was first examined in vitro in microglial cells (primary microglia and BV2 microglial cells) following lipopolysaccharide (LPS) stimulation. LPS induced a time-dependent decrease of miR-124 and upregulated the expression of VAMP3. Manipulating miR-124/VAMP3 expression by using miR-124 mimics or VAMP3-specific siRNA in LPS-stimulated BV2 microglial cells inhibited BV2 microglial activation-associated inflammatory cytokine release. To further examine the role of miR-124/VAMP3 in a surgical setting, we employed a rat surgical trauma model. Significant microglial activation and altered miR-124/VAMP3 expression were observed following surgical trauma. We also altered miR-124/VAMP3 expression in the rat surgical trauma model by administration of exogenous miR-124 and by using electroacupuncture, which is a clinically applicable treatment that modulates microglial function and minimizes postoperative disorders. We determined that electroacupuncture treatment specifically increases the expression of miR-124 in the hypothalamus and hippocampus. Increased miR-124 expression with a concomitant decrease in VAMP3 expression resulted in decreased inflammatory cytokine release related to microglial activation post-surgery. Our study indicates that miR-124/VAMP3 is involved in surgery-induced microglial activation and that targeting miR-124/VAMP3 could be a potential therapeutic strategy for postoperative disorders involving microglial activation.

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Metadata

Authors
Chen, Y., Sun, J.-X., Chen, W.-K., Wu, G.-C., Wang, Y.-Q., Zhu, K.-Y., & Wang, J.
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-08-16
Volume
4
Issue
1
ISSN
2059-3635
DOI
10.1038/s41392-019-0061-x
PMC
PMC6799846
Cited by
74
References
3
Language
en
Licence
Funders
  • China Scholarship Council (201700260280)
  • National Natural Science Foundation of China (81871591, 81202746)

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