title: MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. syelamanchili@unmc.edu
authors.forename: Sowmya V
authors.initials: SV
authors.lastname: Yelamanchili
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Lamberty
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Rennard
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Morsey
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Hochfelder
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Brittney M
authors.initials: BM
authors.lastname: Meays
authors.affiliation: 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.
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000821:virology; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017404:In Situ Hybridization, Fluorescence; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D051199:Toll-Like Receptor 7