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MIR147B: A NOVEL KEY REGULATOR OF IL-1β-MEDIATED INFLAMMATION IN ASTROCYTES
Introduction
A dysregulated inflammatory response is present in various pathologies of the central nervous system (CNS), including epilepsy, which is one of the most common chronic neurological disorders, affecting more than 50 million people worldwide. In the epi- leptogenic brain, astrocytes, which are abundantly present, are considered one of the most important type of glial cells contributing to the neuroinflammatory response 1, 2. Astrocytes can produce various pro-inflammatory mediators, including cytokines and chemokines, which leads to activation of the innate and adaptive immune response 1, 3, 4. Reactive gliosis in epilepsy is also characterized by increased proliferation and aberrant generation of astrocytes from progenitor cells 5, 6. In vitro, this increased proliferation can be induced by treatment with the pro-inflammatory cytokine interleukin-1β (IL-1β) 7, which is a key player in neuroinflammation, and is mainly produced by activated astroglial cells in response to tissue damage, increased neuronal activity 8 or cellular stress 9-11. IL-1β is also highly expressed both in experimental rodent models of epilepsy and in human epileptogenic brain and contributes to seizure generation and epileptogenesis in animal models 1. Among its cellular targets, IL-1β acts on astrocytes by activating the IL-1 recep- tor (IL-1R1), thus leading to NF-κB-mediated transcription of growth factors and various immune-related molecules including cytokines and danger signals 12, 13.
Previous studies indicate that astrocytes also produce a family of microRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, which are crucial modulators of inflammatory pathways linked to various neurological disorders, including epilepsy 14. The expression of several miRNAs, including those associated with neuroinflammatory signals, has been shown to change in human epilepsy and experimental models of epilepsy, providing either targets for treatment or valuable disease biomarkers 15, 16. For example, it was previously reported that miR146a, which is associated with modulation of IL-1R/Toll like receptor 4 signaling, is up-regu- lated in several CNS pathologies including epilepsy, and serves as an important feedback inhibitor of inflammation in astrocytes 17-19. Recently, it has been shown that administra- tion of miR146a in mice developing epilepsy prevented disease progression and reduced seizures 20, indicating that miRNAs related to neuroinflammation could have therapeutic value in epilepsy.
Besides miR146a, there may be other miRNAs that could have therapeutic potential. In order to identify these miRNAs, high throughput, transcriptome wide stud- ies are required. To the best of our knowledge no such study has been performed yet in human astrocytes. Therefore, we studied which miRNAs are produced by fetal human astrocytes during inflammatory conditions in vitro and validated these findings in human epileptogenic brain tissues, in two different epilepsy associated pathologies: Tuberous Sclerosis Complex (TSC; a genetic disorder with focal developmental malformations of the cerebral cortex) and Temporal Lobe Epilepsy with hippocampal sclerosis (TLE-HS; the most common type of symptomatic epilepsy in adults). In addition, we investigated the functional role of two miRNAs, which were differentially expressed by astrocytes upon IL-1β/IL-1R1 activation, on the expression of inflammatory mediators, proliferation and differentiation of fetal human astrocytes and neural stem cells in culture.
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