The role of human endogenous retroviral RNA as an activator of Toll-like receptors in neurodegeneration
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
Human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome, and some HERVs such as HERV-K(HML-2) are discussed to be involved in neurological disorders. However, their biological function remained largely unexplored. Tolllike receptors (TLR) sense pathogen- and host-derived factors, including single-stranded RNA (ssRNA). Within the funding period of the reported project we showed that ssRNA from an HERV-K(HML-2) env gene region activates human TLR8, as well as murine Tlr7, expressed in neurons and microglia, the major immune cells in the brain, thereby causing neurodegeneration. HERV-K(HML-2) RNA introduced into the cerebrospinal fluid (CSF) of either wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration and microglial accumulation. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML- 2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Transcriptome datasets of human AD brain samples revealed distinct correlation of upregulated HERV- K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. In addition to our studies on HERV-K RNA in the context of neurodegenerative diseases such as AD, we investigated whether activation of TLR7 as one of the key endogenous ssRNA-sensing immune receptors, contributes to glioblastoma (GBM), the most frequent brain tumor in adults. We found that activation of TLR7 expressed in microglia through let-7 microRNAs modulates diverse functions of these cells, including the release of inflammatory mediators. These sequence-specific microRNAs are differentially expressed in both human and murine glioma. Moreover, they reduce tumor growth in a sequence-dependent fashion through microglial TLR7 in the murine glioma model GL261. In summary, our data establish endogenous ssRNA including HERV-K(HML-2) RNA and sequence-specific miRNA as ligands for TLR7 and TLR8. The results of our studies imply a contribution of endogenous ssRNA to brain pathologies such as AD and GBM.
Publications
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(2019) let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7. Cell Rep 29:3460-3471
Buonfiglioli, Alice; Efe, Ibrahim E.; Guneykaya, Dilansu; Ivanov, Andranik; Huang, Yimin; Orlowski, Elisabeth; Krüger, Christina; Deisz, Rudolf A.; Markovic, Darko; Flüh, Charlotte; Newman, Andrew G.; Schneider, Ulf C.; Beule, Dieter; Wolf, Susanne A.; Dzaye, Omar; Gutmann, David H.; Semtner, Marcus; Kettenmann, Helmut & Lehnardt, Seija
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(2020) Human endogenous retrovirus HERVK RNA causes neurodegeneration through Toll-like receptors. J Clin Invest Insight 5, pii:131093
Dembny, Paul; Newman, Andrew G.; Singh, Manvendra; Hinz, Michael; Szczepek, Michal; Krüger, Christina; Adalbert, Robert; Dzaye, Omar; Trimbuch, Thorsten; Wallach, Thomas; Kleinau, Gunnar; Derkow, Katja; Richard, Bernhard C.; Schipke, Carola; Scheidereit, Claus; Stachelscheid, Harald; Golenbock, Douglas; Peters, Oliver; Coleman, Michael; ... & Lehnardt, Seija
