title: An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration.
abstract: Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7(−/−) fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Lehmann
authors.forename: Christina
authors.initials: C
authors.lastname: Krüger
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
authors.forename: Katja
authors.initials: K
authors.lastname: Derkow
authors.forename: Karen
authors.initials: K
authors.lastname: Rosenberger
authors.forename: Jan
authors.initials: J
authors.lastname: Baumgart
authors.forename: Thorsten
authors.initials: T
authors.lastname: Trimbuch
authors.forename: Gina
authors.initials: G
authors.lastname: Eom
authors.forename: Michael
authors.initials: M
authors.lastname: Hinz
authors.forename: David
authors.initials: D
authors.lastname: Kaul
authors.forename: Piet
authors.initials: P
authors.lastname: Habbel
authors.forename: Roland
authors.initials: R
authors.lastname: Kälin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzoni
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rybak
authors.forename: Duong
authors.initials: D
authors.lastname: Nguyen
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Veh
authors.forename: Olaf
authors.initials: O
authors.lastname: Ninnemann
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.forename: Eckart
authors.initials: E
authors.lastname: Schott
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: F Gregory
authors.initials: FG
authors.lastname: Wulczyn
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D035683:MicroRNAs; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C542687:mirnlet7 microRNA, mouse