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Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7

Item Type:Article
Title:Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7
Creators Name:Lehmann, S.M. and Rosenberger, K. and Krueger, C. and Habbel, P. and Derkow, K. and Kaul, D. and Rybak, A. and Brandt, C. and Schott, E. and Wulczyn, F.G. and Lehnardt, S.
Abstract:Innate immune receptors represent an evolutionarily ancient system that allows organisms to detect and rapidly respond to pathogen- and host-derived factors. TLRs are predominantly expressed in immune cells and mediate such a response. Although this class of pattern recognition receptors is involved in CNS disorders, the knowledge of ligands leading to activation of TLRs and to subsequent CNS damage is limited. We report in this study that ssRNA causes neurodegeneration and neuroinflammation dependent on TLR7 in the CNS. TLR7 is not only expressed in microglia, the major immune cells of the brain, but also in neurons of the CNS. Extracellularly delivered ssRNA40, an oligoribonucleotide derived from HIV and an established ligand of TLR7, induces neuronal cell death dependent on TLR7 and the central adapter molecule MyD88 in vitro. Activation of caspase-3 is involved in neuronal damage mediated by TLR7. This cell-autonomous neuronal cell death induced by ssRNA40 is amplified in the presence of microglia that mount an inflammatory response to ssRNA40 through TLR7. Intrathecal administration of ssRNA40 causes widespread neurodegeneration in wild-type but not in TLR7(-/-) mice, confirming that neuronal cell death induced by ssRNA40 through TLR7 occurs in vivo. Our results point to a possible mechanism through which extracellularly delivered ssRNA contributes to CNS damage and determine an obligatory role for TLR7 in this pathway.
Keywords:Caspase 3, Cell Death, Extracellular Fluid, HEK293 Cells, HIV, Inbred C57BL Mice, Knockout Mice, Membrane Glycoproteins, Myeloid Differentiation Factor 88, Neurodegenerative Diseases, Primary Cell Culture, Signal Transduction, Spinal Injections, Toll-Like Receptor 7, Tumor Cell Line, Viral RNA, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:189
Number:3
Page Range:1448-1458
Date:1 August 2012
Official Publication:https://doi.org/10.4049/jimmunol.1201078
PubMed:View item in PubMed

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