Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration

Authors

• Guoku Hu, University of Nebraska Medical CenterFollow
• Ke Liao, University of Nebraska Medical Center
• Fang Niu, University of Nebraska Medical CenterFollow
• Lu Yang, University of Electronic Science and Technology of China
• Blake W. Dallon, University of Nebraska Medical Center
• Shannon E. Callen, University of Nebraska Medical CenterFollow
• Changhai Tian, University of Nebraska Medical CenterFollow
• Jiang Shu, University of Nebraska-LincolnFollow
• Juan Cui, University of Nebraska-LincolnFollow
• Zhiqiang Sun, University of Nebraska Medical CenterFollow
• Yuri L. Lyubchenko, University of Nebraska Medical CenterFollow
• Minhan Ka, Korea Institute of Toxicology
• Xian-Ming Chen, Creighton University School of Medicine
• Shilpa Buch, University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

2018

Citation

Molecular Therapy: Nucleic Acids Vol. 13

Comments

Copyright 2018 The Authors.

Open access

https://doi.org/10.1016/j.omtn.2018.09.019

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 kB (NF-kB) 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.