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
- (2019) let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7. Cell Rep 29:3460-3471
Buonfiglioli A, Efe IE, Guneykaya D, Ivanov A, Huang Y, Orlowski E, Krüger C, Deisz RA, Markovic D, Flüh C, Newman AG, Schneider UC, Beule D, Wolf SA, Dzaye O, Gutmann DH, Semtner M, Kettenmann H, Lehnardt S
(See online at https://doi.org/10.1016/j.celrep.2019.11.029) - (2020) Human endogenous retrovirus HERVK RNA causes neurodegeneration through Toll-like receptors. J Clin Invest Insight 5, pii:131093
Dembny P, Newman AG, Singh M, Hinz, M, Szczepek, M, Krüger, C, Adalbert, R, Dzaye, O, Trimbuch, T, Wallach, T, Kleinau, G, Derkow, K, . Richard, BC, Schipke, C, Scheidereit, C, Stachelscheid, H, Golenbock, D, Peters, O, Coleman, M, Heppner, FL, Scheerer, P, Tarabykin, V, Ruprecht, K, Izsvák Z, Mayer J, Lehnardt S
(See online at https://doi.org/10.1172/jci.insight.131093)
