Previous studies have shown that Toll-like receptors (TLRs) on neurons and glia can cause CNS damage through mechanisms that are not pathogen-induced, but the identity of these alternative triggers remained elusive. Lehnardt and colleagues now show that the microRNA (miRNA) let-7 can act as a potent activator of TLR7 signalling in neurons and that this activation can induce neurodegeneration, thus also revealing a new role of miRNAs beyond their function as regulators of gene expression.
let-7 is one of the most abundant miRNAs expressed in the human brain, and its sequence contains a core GU-rich motif that is also present in the single-stranded RNA40, which is a known ligand for TLR7. Thus, the authors hypothesized that let-7 can activate this receptor.
Preliminary experiments in microglia and macrophages indicated that synthetic let-7 can directly activate TLR7. Furthermore, exposure of extracellular let-7 to purified cortical and hippocampal neurons induced dose-dependent and time-dependent cell death. let-7, however, did not induce cell death in cortical neurons derived from Tlr7−/− mice. Interestingly, exposure of extracellular let-7 to co-cultures of neurons and microglia or neurons and astrocytes did not enhance neuronal cell death, which indicates that non-neuronal cells are not necessary for let-7-induced neuronal cell death.
The authors subsequently showed that the addition of culture supernatants from apoptotic or necrotic neurons (in which high levels of let-7 were detected) to fresh primary neurons induced injury and loss, an effect that could be abrogated by pretreatment of neurons with a let-7 inhibitor. These in vitro results were recapitulated in vivo, as intrathecal injection of let-7 into mice induced time-dependent axonal injury and neuronal (both cortical and striatal) loss, and these effects were blocked by pretreatment with a let-7 inhibitor.
Together, these data uncover a new role of miRNAs as endogenous activators of TLRs in microglia and neurons, and also imply that TLRs function as death receptors in neurons under pathological conditions.
ORIGINAL RESEARCH PAPER
Lehmann, S. M. et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nature Neurosci. 15, 827–835 (2012)
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Tse, M. Uncovering new roles for microRNAs and TLRs. Nat Rev Neurosci 13, 449 (2012). https://doi.org/10.1038/nrn3276
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DOI: https://doi.org/10.1038/nrn3276