Toll-like receptors (TLRs) are implicated in noninfectious injury of the brain, such as that caused by neurodegenerative diseases, stroke, or multiple sclerosis. TLR7, an innate immune receptor localized to endosomes, recognizes various forms of pathogen-derived RNA. Noting that the let-7 family of microRNAs, which are abundant in the brain, had a GU-rich sequence similar to that of a single-stranded RNA from human immunodeficiency virus that activates TLR7, Lehmann et al. showed that extracellular addition of let-7 microRNAs stimulated the production of a cytokine from cultured microglia and macrophages. This response depended on the conserved GU-rich sequence and was reduced in TLR7-deficient cells. In situ hybridization and immunohistochemistry demonstrated that TLR7 was present in neurons in mouse brain. Adding let-7 to purified cortical or hippocampal neurons triggered caspase-dependent cell death. Cells deficient in TLR7 or its adaptor protein MyD88 were resistant to let-7–induced neurotoxicity. Biotinylated let-7 was taken up by neurons without the presence of transfection reagents, confirming that extracellularly applied let-7 was internalized and reached the endosomally localized TLR7. Supernatants of neurons induced to die by either apoptosis or necrosis contained let-7 and caused cell death when applied to cultured neurons. Cell death was prevented if the neurons receiving the supernatant lacked TLR7 or if the supernatants were pretreated with a let-7 family inhibitor. TLR7-dependent neuronal injury and loss after intrathecal injection of let-7 confirmed its neurotoxicity in vivo. TLR7-deficient mice that had TLR7 reintroduced by in utero electroporation exhibited a specific reduction in a marker of transfection after injection of let-7, consistent with TLR7-dependent toxicity. Analysis of the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease showed increased let-7 abundance compared with the amount in CSF from control patients. Thus, let-7 may contribute to neuronal loss as it is released from dying cells and causes neurotoxicity in nearby cells.
S. M. Lehmann, C. Krüger, B. Park, K. Derkow, K. Rosenberger, J. Baumgart, T. Trimbuch, G. Eom, M. Hinz, D. Kaul, P. Habbel, R. Kälin, E. Franzoni, A. Rybak, D. Nguyen, R. Veh, O. Ninnemann, O. Peters, R. Nitsch, F. L. Heppner, D. Golenbock, E. Schott, H. L Ploegh, F. G. Wulczyn, S. Lehnardt, An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 15, 827–835 (2012). [PubMed]