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

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.