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Extracellularly Delivered Single-Stranded Viral RNA Causes Neurodegeneration Dependent on TLR7

Lehmann, Sabrina M, Rosenberger, Karen, Krüger, Christina, Habbel, Piet, Derkow, Katja, Kaul, David, Rybak, Agnieszka, Brandt, Christine, Schott, Eckart, Wulczyn, F Gregory, Lehnardt, Seija·2012·The Journal of Immunology
DOI 10.4049/jimmunol.1201078
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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.

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Metadata

Authors
Lehmann, S. M., Rosenberger, K., Krüger, C., Habbel, P., Derkow, K., Kaul, D., Rybak, A., Brandt, C., Schott, E., Wulczyn, F. G., & Lehnardt, S.
Affiliations
  • Department of Neurology, Charity University Medicine Berlin , 10117 Berlin,
  • Max Delbrück Center for Molecular Medicine Berlin-Buch , 13092 Berlin,
  • Institute of Cell Biology and Neurobiology, Center for Anatomy, Charity University Medicine Berlin , 10117 Berlin,
  • Department of Hepatology and Gastroenterology, Charity University Medicine Berlin , 13353 Berlin,
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2012-08-01
Volume
189
Issue
3
Pages
1448-1458
ISSN
  • 0022-1767
  • 1550-6606
DOI
10.4049/jimmunol.1201078
Cited by
64
References
1
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)

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