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MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response
Anand Iyer1, Emanuele Zurolo, Avanita Prabowo
1Department of Neuro-Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract:
Increasing evidence supports the involvement of microRNAs (miRNA) in the regulation of inflammation in human neurological disorders. In the present study we investigated the role of miR-146a, a key regulator of the innate immune response, in the modulation of astrocyte-mediated inflammation. Using Taqman PCR and in situ hybridization, we studied the expression of miR-146a in epilepsy-associated glioneuronal lesions which are characterized by prominent activation of the innate immune response. In addition, cultured human astrocytes were used to study the regulation of miR-146a expression in response to proinflammatory cytokines. qPCR and western blot were used to evaluate the effects of overexpression or knockdown of miR-146a on IL-1β signaling. Downstream signaling in the IL-1β pathway, as well as the expression of IL-6 and COX-2 were evaluated by western blot and ELISA. Release several cytokines was evaluated using a human magnetic multiplex cytokine assay on a Luminex® 100™/200™ platform. Increased expression of miR-146a was observed in glioneuronal lesions by Taqman PCR. MiR-146a expression in human glial cell cultures was strongly induced by IL-1β and blocked by IL-1β receptor antagonist. Modulation of miR-146a expression by transfection of astrocytes with anti-miR146a or mimic, regulated the mRNA expression levels of downstream targets of miR-146a (IRAK-1, IRAK-2 and TRAF-6) and the expression of IRAK-1 protein. In addition, the expression of IL-6 and COX-2 upon IL-1β stimulation was suppressed by increased levels of miR-146a and increased by the reduction of miR-146a. Modulation of miR-146a expression affected also the release of several cytokines such as IL-6 and TNF-α. Our observations indicate that in response to inflammatory cues, miR-146a was induced as a negative-feedback regulator of the astrocyte-mediated inflammatory response. This supports an important role of miR-146a in human neurological disorders associated with chronic inflammation and suggests that this miR may represent a novel target for therapeutic strategies.
Insights
MicroRNA-146a (miR-146a) acts as a negative feedback regulator in astrocyte inflammation, crucial for neurological disorders. Upregulation of miR-146a suppresses inflammatory responses, suggesting therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are increasingly recognized for their role in regulating inflammation within human neurological disorders.
- Astrocyte-mediated inflammation is a key component of the innate immune response in the central nervous system.
- miR-146a is a critical microRNA involved in modulating innate immune responses.
Purpose of the Study:
- To investigate the role of miR-146a in regulating astrocyte-mediated inflammation.
- To examine miR-146a expression in epilepsy-associated glioneuronal lesions.
- To determine the impact of miR-146a modulation on inflammatory signaling pathways in astrocytes.
Main Methods:
- Taqman PCR and in situ hybridization were used to assess miR-146a expression in tissue samples.
- Primary human astrocyte cultures were treated with proinflammatory cytokines (e.g., IL-1β) to study miR-146a regulation.
- Quantitative PCR (qPCR), Western blot, ELISA, and multiplex cytokine assays were employed to evaluate signaling pathways and cytokine release.
- Astrocytes were transfected with miR-146a mimics or inhibitors to modulate its expression.
Main Results:
- miR-146a expression was significantly increased in glioneuronal lesions associated with epilepsy.
- Proinflammatory cytokine IL-1β strongly induced miR-146a expression in cultured human astrocytes.
- Modulation of miR-146a levels affected the expression of key inflammatory mediators, including IL-6 and COX-2.
- Overexpression of miR-146a suppressed IL-1β signaling and the release of cytokines like IL-6 and TNF-α, while knockdown had the opposite effect.
Conclusions:
- miR-146a functions as a negative-feedback regulator of astrocyte-mediated inflammatory responses.
- The findings highlight the significant role of miR-146a in neurological disorders characterized by chronic inflammation.
- miR-146a represents a potential novel therapeutic target for managing neuroinflammation.
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