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Published on: September 7, 2010
miR-154-5p Is a Novel Endogenous Ligand for TLR7 Inducing Microglial Activation and Neuronal Injury
Hugo McGurran1,2, Victor Kumbol1,2, Christina Krüger2
1Charité-Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, 10117 Berlin, Germany.
Abstract:
Toll-like receptors (TLRs) are a collection of pattern recognition sensors that form a first line of defence by detecting pathogen- or damage-associated molecular patterns and initiating an inflammatory response. TLR activation in microglia, the major immune cells in the brain, can trigger the release of inflammatory molecules, which may contribute to various CNS diseases including Alzheimer's disease. Recently, some microRNAs were shown to serve as signalling molecules for TLRs. Here, we present miR-154-5p as a novel TLR7 ligand. Exposing microglia to miR-154-5p results in cytokine release and alters expression of the TLR signalling pathway dependent on TLR7. Additionally, miR-154-5p causes neuronal injury in enriched cortical neuron cultures and additive toxicity in the presence of microglia. Finally, intrathecal injection of miR-154-5p into mice leads to neuronal injury and accumulation of microglia in the cerebral cortex dependent on TLR7 expression. In conclusion, this study establishes miR-154-5p as a direct activator of TLR7 that can cause neuroinflammation and neuronal injury, which may contribute to CNS disease.
Insights
MicroRNA-154-5p directly activates Toll-like receptor 7 (TLR7), triggering neuroinflammation and neuronal injury. This discovery offers new insights into central nervous system (CNS) diseases like Alzheimer's.
Area of Science:
- Neuroimmunology
- Molecular Biology
- MicroRNA Therapeutics
Background:
- Toll-like receptors (TLRs) are crucial pattern recognition sensors initiating inflammatory responses.
- Microglial TLR activation contributes to central nervous system (CNS) diseases, including Alzheimer's disease.
- MicroRNAs are emerging as signaling molecules in TLR pathways.
Purpose of the Study:
- To identify novel microRNAs acting as signaling molecules for TLRs.
- To investigate the role of miR-154-5p as a potential TLR7 ligand.
- To determine the impact of miR-154-5p on neuroinflammation and neuronal injury.
Main Methods:
- Microglia and cortical neuron cultures were exposed to miR-154-5p.
- TLR signaling pathway alterations were analyzed.
- Intrathecal injections of miR-154-5p were performed in mice.
- Neuronal injury and microglial accumulation were assessed.
Main Results:
- miR-154-5p was identified as a direct ligand for TLR7.
- miR-154-5p induced cytokine release and altered TLR7-dependent signaling in microglia.
- miR-154-5p caused neuronal injury in vitro and in vivo.
- In vivo, miR-154-5p led to microglial accumulation in the cerebral cortex.
Conclusions:
- miR-154-5p is a novel direct activator of TLR7.
- TLR7 activation by miR-154-5p promotes neuroinflammation and neuronal injury.
- This pathway may contribute to the pathogenesis of CNS diseases.
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