@article{Wallach-2021,
author = {Wallach, Thomas and Mossmann, Zoe and Szczepek, Michal and Wetzel, Max and  Machado, Rui and  Raden, Martin and  Miladi, Milad and  Kleinau, Gunnar and Krüger, Christina and Dembny, Paul and  Adler, Drew and Zhai, Yuanyuan and  Dzaye, Omar and Futschik, Matthias and Backofen, Rolf and Scheerer, Patrick and Lehnardt, Seija},
title = {MicroRNA-100-5p and microRNA-298-5p released from apoptotic cortical neurons are endogenous Toll-like receptor 7/8 ligands that contribute to neurodegeneration},
journal = {Molecular Neurodegeneration},
year = {2021},
doi = {10.1186/s13024-021-00498-5},
volume = {16},
user = {mmann},
publisher = {Sprinter Nature},
number = {80},
issn = {1664-302X},
abstract = {Results: We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/ chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling. 
            Conclusion: Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration.
            Keywords: Extracellular microRNAs, Endogenous Toll-like receptor ligands, Cortical neurons, Neuronal apoptosis, Microglia, Neurodegeneration, miRNA microarray}
}