An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration

Sabrina M. Lehmann; Christina Krüger; Boyoun Park; Katja Derkow; Karen Rosenberger; Jan Baumgart; Thorsten Trimbuch; Gina Eom; Michael Hinz; David Kaul; Piet Habbel; Roland Kälin; Eleonora Franzoni; Agnieszka Rybak; Duong Nguyen; Rüdiger Veh; Olaf Ninnemann; Oliver Peters; Robert Nitsch; Frank L. Heppner; Douglas Golenbock; Eckart Schott; Hidde L. Ploegh; F. Gregory Wulczyn; Seija Lehnardt

doi:10.1038/nn.3113

An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration

Sabrina M. Lehmann, Christina Krüger, Boyoun Park, Katja Derkow, Karen Rosenberger, Jan Baumgart, Thorsten Trimbuch, Gina Eom, Michael Hinz, David Kaul, Piet Habbel, Roland Kälin, Eleonora Franzoni, Agnieszka Rybak, Duong Nguyen, Rüdiger Veh, Olaf Ninnemann, Oliver Peters, Robert Nitsch, Frank L. HeppnerDouglas Golenbock, Eckart Schott, Hidde L. Ploegh, F. Gregory Wulczyn, Seija Lehnardt

Research output: Contribution to journal › Article › peer-review

581 Citations (Scopus)

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.

Original language	English
Pages (from-to)	827-835
Number of pages	9
Journal	Nature Neuroscience
Volume	15
Issue number	6
DOIs	https://doi.org/10.1038/nn.3113
Publication status	Published - 2012 Jun

Bibliographical note

Funding Information:
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.).

All Science Journal Classification (ASJC) codes

Neuroscience(all)

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10.1038/nn.3113

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Lehmann, S. M., Krüger, C., Park, B., Derkow, K., Rosenberger, K., Baumgart, J., Trimbuch, T., Eom, G., Hinz, M., Kaul, D., Habbel, P., Kälin, R., Franzoni, E., Rybak, A., Nguyen, D., Veh, R., Ninnemann, O., Peters, O., Nitsch, R., ... Lehnardt, S. (2012). An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nature Neuroscience, 15(6), 827-835. https://doi.org/10.1038/nn.3113

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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.",

author = "Lehmann, {Sabrina M.} and Christina Kr{\"u}ger and Boyoun Park and Katja Derkow and Karen Rosenberger and Jan Baumgart and Thorsten Trimbuch and Gina Eom and Michael Hinz and David Kaul and Piet Habbel and Roland K{\"a}lin and Eleonora Franzoni and Agnieszka Rybak and Duong Nguyen and R{\"u}diger Veh and Olaf Ninnemann and Oliver Peters and Robert Nitsch and Heppner, {Frank L.} and Douglas Golenbock and Eckart Schott and Ploegh, {Hidde L.} and Wulczyn, {F. Gregory} and Seija Lehnardt",

note = "Funding Information: 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. L{\"u}decke and J. Sch{\"u}ler 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.).",

year = "2012",

month = jun,

doi = "10.1038/nn.3113",

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Lehmann, SM, Krüger, C, Park, B, Derkow, K, Rosenberger, K, Baumgart, J, Trimbuch, T, Eom, G, Hinz, M, Kaul, D, Habbel, P, Kälin, R, Franzoni, E, Rybak, A, Nguyen, D, Veh, R, Ninnemann, O, Peters, O, Nitsch, R, Heppner, FL, Golenbock, D, Schott, E, Ploegh, HL, Wulczyn, FG & Lehnardt, S 2012, 'An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration', Nature Neuroscience, vol. 15, no. 6, pp. 827-835. https://doi.org/10.1038/nn.3113

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T2 - Let-7 activates Toll-like receptor 7 and causes neurodegeneration

AU - Lehmann, Sabrina M.

AU - Krüger, Christina

AU - Park, Boyoun

AU - Derkow, Katja

AU - Rosenberger, Karen

AU - Baumgart, Jan

AU - Trimbuch, Thorsten

AU - Eom, Gina

AU - Hinz, Michael

AU - Kaul, David

AU - Habbel, Piet

AU - Kälin, Roland

AU - Franzoni, Eleonora

AU - Rybak, Agnieszka

AU - Nguyen, Duong

AU - Veh, Rüdiger

AU - Ninnemann, Olaf

AU - Peters, Oliver

AU - Nitsch, Robert

AU - Heppner, Frank L.

AU - Golenbock, Douglas

AU - Schott, Eckart

AU - Ploegh, Hidde L.

AU - Wulczyn, F. Gregory

AU - Lehnardt, Seija

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N2 - 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.

AB - 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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An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration

Abstract

Bibliographical note

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