MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease

PLoS Pathogens

Sowmya V. Yelamanchili¹  Howard S. Fox¹  Colleen G. Hochfelder¹  Deborah A. Rennard¹  Brittney M. Meays¹  Benjamin G. Lamberty¹  Brenda M. Morsey¹  Efrat Levy² 

[1] Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America;Nathan S. Kline Institute, Orangeburg, New York, Departments of Pathology, Psychiatry, and Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York, United States of America

关键词: Neurons;    MicroRNAs;    Neuronal death;    Central nervous system;    SIV;    Macrophages;    Toll-like receptors;    Macaque;   

DOI  :  10.1371/journal.ppat.1005032

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In the present study, we isolated and characterized EVs from the brains of rhesus macaques, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed increased miR-21 levels in EVs from SIV encephalitic (SIVE) brains. In situ hybridization revealed increased miR-21 expression in neurons and macrophage/microglial cells/nodules during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into EVs and is neurotoxic when compared to EVs derived from miR-21-/- knockout animals. A mutation of the sequence within miR-21, predicted to bind TLR7, eliminates this neurotoxicity. Indeed miR-21 in EV activates TLR7 in a reporter cell line, and the neurotoxicity is dependent upon TLR7, as neurons isolated from TLR7-/- knockout mice are protected from neurotoxicity. Further, we show that EVs isolated from the brains of monkeys with SIV induced CNS disease activates TLR7 and were neurotoxic when compared to EVs from control animals. Finally, we show that EV-miR-21 induced neurotoxicity was unaffected by apoptosis inhibition but could be prevented by a necroptosis inhibitor, necrostatin-1, highlighting the actions of this pathway in a growing number of CNS disorders.

【 授权许可】

CC BY