title: Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7.
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.
authors: Department of Neurology, Charity University Medicine Berlin, 10117 Berlin, Germany.
authors: Sabrina M
authors: SM
authors: Lehmann
authors: Karen
authors: K
authors: Rosenberger
authors: Christina
authors: C
authors: Krüger
authors: Piet
authors: P
authors: Habbel
authors: Katja
authors: K
authors: Derkow
authors: David
authors: D
authors: Kaul
authors: Agnieszka
authors: A
authors: Rybak
authors: Christine
authors: C
authors: Brandt
authors: Eckart
authors: E
authors: Schott
authors: F Gregory
authors: FG
authors: Wulczyn
authors: Seija
authors: S
authors: Lehnardt
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000009:adverse effects / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D045604:Extracellular Fluid / Q000276:immunology* / Q000821:virology*; D057809:HEK293 Cells; D006678:HIV / Q000235:genetics / Q000276:immunology; D006801:Humans; D007278:Injections, Spinal; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000009:adverse effects / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D061251:Primary Cell Culture; D012367:RNA, Viral / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012367:RNA, Viral; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D053148:Caspase 3