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

Yan Chen; Jing-Xian Sun; Wan-Kun Chen; Gen-Cheng Wu; Yan-Qing Wang; Ke-Ying Zhu; Jun Wang

doi:10.1038/s41392-019-0061-x

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

Signal Transduct Target Ther. 2019 Aug 16:4:27. doi: 10.1038/s41392-019-0061-x. eCollection 2019.

Authors

Yan Chen^{1

2

3}, Jing-Xian Sun^{1

2

3}, Wan-Kun Chen^{4

5}, Gen-Cheng Wu^{1

2

3}, Yan-Qing Wang^{1

2

3}, Ke-Ying Zhu^{1

6}, Jun Wang^{1

2

3}

Affiliations

¹ 1Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Science, Fudan University, 200032 Shanghai, China.
² 2Institutes of Brain Science, Collaborative Innovation Center for Brain Science, Fudan University, 200032 Shanghai, China.
³ 3Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Fudan University, 200032 Shanghai, China.
⁴ 4Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032 Shanghai, China.
⁵ 5Department of Oncology, Shanghai Medical College, Fudan University, 200032 Shanghai, China.
⁶ 6Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.

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.

Keywords: Experimental models of disease; Immunological disorders; Neuroimmunology.

Publication types

Research Support, Non-U.S. Gov't