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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.

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Figure 1: let-7b induces the release of TNF-α from microglia and macrophages via TLR7.
Figure 2: Expression of TLR7 in the CNS.
Figure 3: Extracellular let-7 induces neurodegeneration via TLR7, MyD88 and caspase-3.
Figure 4: let-7 released from dying neurons induces neurodegeneration in vitro.
Figure 5: Intrathecal administration of let-7 causes TLR7-dependent neurodegeneration in the presence or absence of microglia.
Figure 6: Reconstitution of TLR7 restores the neurodegenerative effect of let-7.
Figure 7: CSF of Alzheimer's disease patients contains increased amounts of let-7b.

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Acknowledgements

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.).

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S.L., H.L.P., F.G.W. and E.S. conceived the study and wrote the manuscript. R.K., R.V., O.N., R.N., F.L.H. and D.G. planned the experiments. S.M.L., C.K., B.P., K.D., K.R., J.B., T.T., M.H., G.E., D.K., P.H., E.F., A.R., D.N. and O.P. planned and carried out the experiments.

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Correspondence to Seija Lehnardt.

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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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