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Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression
Xian Xian1, Li-Li Cai1, Yang Li1
1Department of Radiology, Affiliated Hospital of Jiangsu University, No. 438, Jiefang Road, Zhenjiang, 212001, Jiangsu, China.
Background:
Neuroinflammation is an important component mechanism in the development of depression. Exosomal transfer of MDD-associated microRNAs (miRNAs) from neurons to microglia might exacerbate neuronal cell inflammatory injury.
Results:
By sequence identification, we found significantly higher miR-9-5p expression levels in serum exosomes from MDD patients than healthy control (HC) subjects. Then, in cultured cell model, we observed that BV2 microglial cells internalized PC12 neuron cell-derived exosomes while successfully transferring miR-9-5p. MiR-9-5p promoted M1 polarization in microglia and led to over releasing of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which exacerbated neurological damage. Furthermore, we identified suppressor of cytokine signaling 2 (SOCS2) as a direct target of miR-9-5p. Overexpression of miR-9-5p suppressed SOCS2 expression and reactivated SOCS2-repressed Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways. Consistently, we confirmed that adeno-associated virus (AAV)-mediated overexpression of miR-9-5p polarized microglia toward the M1 phenotype and exacerbated depressive symptoms in chronic unpredictable mild stress (CUMS) mouse mode.
Conclusion:
MiR-9-5p was transferred from neurons to microglia in an exosomal way, leading to M1 polarization of microglia and further neuronal injury. The expression and secretion of miR-9-5p might be novel therapeutic targets for MDD.
Insights
MicroRNAs (miRNAs) in exosomes transfer from neurons to microglia, worsening depression. Targeting miR-9-5p offers a potential therapeutic strategy for major depressive disorder (MDD).
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Neuroinflammation plays a key role in depression development.
- Exosomal transfer of microRNAs (miRNAs) from neurons to microglia may worsen neuronal inflammatory injury in major depressive disorder (MDD).
Purpose of the Study:
- To investigate the role of exosomal miR-9-5p transfer from neurons to microglia in MDD.
- To explore miR-9-5p as a potential therapeutic target for MDD.
Main Methods:
- Serum exosome analysis in MDD patients and healthy controls (HC).
- In vitro cell models (BV2 microglia, PC12 neurons) to study exosome uptake and miRNA transfer.
- In vivo mouse model (chronic unpredictable mild stress - CUMS) to assess miR-9-5p effects on depressive symptoms and neuroinflammation.
- Molecular analyses including cytokine measurement, target gene identification (SOCS2), and pathway analysis (JAK/STAT3).
Main Results:
- Serum exosome levels of miR-9-5p were significantly higher in MDD patients than HC.
- Neuron-derived exosomes transferred miR-9-5p to microglia, promoting M1 polarization and release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).
- miR-9-5p targeted SOCS2, suppressing its expression and reactivating JAK/STAT3 pathways, exacerbating neurological damage and depressive symptoms in a mouse model.
Conclusions:
- Exosomal miR-9-5p transfer from neurons to microglia induces M1 polarization and neuronal injury, contributing to MDD.
- miR-9-5p expression and secretion represent novel therapeutic targets for MDD.
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