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

Sowmya V Yelamanchili, Benjamin G. Lamberty, Deborah A. Rennard, Brenda M. Morsey, Colleen G. Hochfelder, Brittney M. Meays, Efrat Levy, Howard S Fox

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005032
JournalPLoS pathogens
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2015

Fingerprint

Simian Immunodeficiency Virus
Virus Diseases
Central Nervous System Diseases
Brain
Macrophages
RNA Sequence Analysis
Extracellular Vesicles
Neurons
Macaca mulatta
Knockout Mice
Haplorhini
In Situ Hybridization
Apoptosis
Cell Line
Mutation

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease. / Yelamanchili, Sowmya V; Lamberty, Benjamin G.; Rennard, Deborah A.; Morsey, Brenda M.; Hochfelder, Colleen G.; Meays, Brittney M.; Levy, Efrat; Fox, Howard S.

In: PLoS pathogens, Vol. 11, No. 7, e1005032, 01.07.2015.

Research output: Contribution to journalArticle

Yelamanchili, Sowmya V ; Lamberty, Benjamin G. ; Rennard, Deborah A. ; Morsey, Brenda M. ; Hochfelder, Colleen G. ; Meays, Brittney M. ; Levy, Efrat ; Fox, Howard S. / MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease. In: PLoS pathogens. 2015 ; Vol. 11, No. 7.
@article{fcb07fd79b434c459eb95dd639756ea6,
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.",
author = "Yelamanchili, {Sowmya V} and Lamberty, {Benjamin G.} and Rennard, {Deborah A.} and Morsey, {Brenda M.} and Hochfelder, {Colleen G.} and Meays, {Brittney M.} and Efrat Levy and Fox, {Howard S}",
year = "2015",
month = "7",
day = "1",
doi = "10.1371/journal.ppat.1005032",
language = "English (US)",
volume = "11",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease

AU - Yelamanchili, Sowmya V

AU - Lamberty, Benjamin G.

AU - Rennard, Deborah A.

AU - Morsey, Brenda M.

AU - Hochfelder, Colleen G.

AU - Meays, Brittney M.

AU - Levy, Efrat

AU - Fox, Howard S

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84938810279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938810279&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1005032

DO - 10.1371/journal.ppat.1005032

M3 - Article

C2 - 26154133

AN - SCOPUS:84938810279

VL - 11

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 7

M1 - e1005032

ER -