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Mechanisms of M2 Macrophage-Derived Exosomal Long Non-coding RNA PVT1 in Regulating Th17 Cell Response in
Lei Wu1, Jinjin Xia2, Donghui Li2
1Department of Neurology, The Second Affiliated Hospital of Zhejiang, University School of Medicine, Hangzhou, China.
Abstract:
Long non-coding RNA (lncRNA) is pivotal for multiple sclerosis (MS), but the potential mechanism of lncRNA PVT1 in MS animal model, experimental autoimmune encephalomyelitis (EAE) still remains unclear. In this study, macrophages were firstly isolated and induced to polarize into M2 macrophages. M2 macrophage-derived exosomes (M2-exos) were extracted and identified, and EAE mouse model was established and treated with M2-exos. The effect of M2-exos on EAE mice was evaluated by clinical scores. The proportion of Treg and Th17 cells in spinal cord cells and splenocytes, and levels of inflammatory factors were measured. The targeting relationships among PVT1, miR-21-5p, and SOCS5 were verified. The expression of JAKs/STAT3 pathway-related proteins was measured. After M2-exo treatment, the clinical score of EAE mice decreased, and demyelination and inflammatory infiltration improved; Th17 cells decreased, Treg cells increased, and the levels of inflammatory factors decreased significantly. SOCS5 and PVT1 were downregulated and miR-21-5p was upregulated in EAE mice. PVT1 could sponge miR-21-5p to regulate SOCS5. SOCS5 alleviated EAE symptoms by repressing the JAKs/STAT3 pathway. Together, M2-exos-carried lncRNA PVT1 sponged miR-21-5p to upregulate SOCS5 and inactivate the JAKs/STAT3 pathway, thus reducing inflammation and protecting EAE mice. This study may offer novel treatments for MS.
Insights
M2 exosomes carrying long non-coding RNA PVT1 reduce inflammation in experimental autoimmune encephalomyelitis (EAE) mice by regulating the miR-21-5p/SOCS5 axis and inhibiting the JAKs/STAT3 pathway, offering potential new treatments for multiple sclerosis (MS).
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Long non-coding RNAs (lncRNAs) play a crucial role in the pathogenesis of multiple sclerosis (MS).
- The specific mechanism of lncRNA PVT1 in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS is not well understood.
- Macrophages and their derived exosomes are involved in immune regulation and tissue repair.
Purpose of the Study:
- To investigate the therapeutic potential of M2 macrophage-derived exosomes (M2-exos) in an EAE mouse model.
- To elucidate the molecular mechanism of lncRNA PVT1 carried by M2-exos in regulating inflammation and immune responses in EAE.
- To explore the targeting relationship between PVT1, miR-21-5p, and SOCS5, and their impact on the JAKs/STAT3 pathway.
Main Methods:
- Isolation and M2 polarization of macrophages, followed by extraction and identification of M2-exos.
- Establishment of an EAE mouse model and treatment with M2-exos.
- Evaluation of clinical scores, immune cell proportions (Treg, Th17), inflammatory factor levels, gene/protein expression (PVT1, miR-21-5p, SOCS5, JAKs/STAT3 pathway), and verification of targeting relationships.
Main Results:
- M2-exo treatment significantly improved clinical scores, reduced demyelination and inflammatory infiltration in EAE mice.
- M2-exos treatment led to decreased Th17 cells, increased Treg cells, and reduced levels of inflammatory factors.
- M2-exos treatment upregulated SOCS5 and downregulated PVT1 and miR-21-5p in EAE mice; PVT1 sponged miR-21-5p to regulate SOCS5, which inhibited the JAKs/STAT3 pathway.
Conclusions:
- M2-exos-carried lncRNA PVT1 acts as a therapeutic agent in EAE by sponging miR-21-5p, upregulating SOCS5, and inactivating the JAKs/STAT3 pathway.
- This mechanism effectively reduces inflammation and protects against EAE progression.
- The findings suggest a novel therapeutic strategy for MS utilizing M2-exos and their cargo.
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