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.
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We thank M. Brinkmann (Helmholtz Centre for Infection Research) for providing immortalized bone marrow–derived macrophages. We also thank C. Schipke, A.-M. Rohde, D. Lüdecke and J. Schüler for helpful discussions and excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft SFB-TRR43/A1 and NeuroCure Exc 257 (to S.L.), SFB-TRR43/A6 (to F.L.H.), and by SFB665/A2 and GRK1123 (to F.G.W.).
The authors declare no competing financial interests.
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Lehmann, S., Krüger, C., Park, B. et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15, 827–835 (2012). https://doi.org/10.1038/nn.3113
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