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Identification of the microglia-associated signature in experimental autoimmune encephalomyelitis
Yan Wu1, Jianhong Wang1,2, Bo Chen3
1Neurology Department, First Affiliated Hospital of Kunming Medical University, Kunming, China.
Background:
Multiple sclerosis (MS) is a chronic neuroinflammatory disorder characterized by demyelination and immune dysregulation, and microglia play a central role in disease progression. Despite this, the specific microglial gene signatures contributing to MS remain inadequately characterized.
Methods:
We utilized an experimental autoimmune encephalomyelitis (EAE) mouse model and performed RNA sequencing to identify differentially expressed Messenger RNAs (DEmRNAs), Long Non-Coding RNAs (DElncRNAs), Circular RNAs (DEcircRNAs), and microRNAs (DEmiRNAs) in microglia. A machine learning approach incorporating five distinct algorithms was applied to select a robust multigene signature. The biological functions of the included genes were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and validated by quantitative reverse transcription PCR (qRT-PCR). Additionally, molecular docking studies were conducted to explore potential interactions with approved MS therapeutics.
Results:
Six DEmRNAs were identified as key microglia-associated biomarkers: Neutrophilic Granule Protein (NGP), Histone Cluster 1 H2B Family Member J (HIST1H2BJ), Phenazine Biosynthesis-Like Domain-Containing Protein 1 (PBLD1), Muscleblind-Like Protein 3 (MBNL3), Lymphocyte Antigen 180 (CD180), and Coagulation Factor X (F10). All six genes were found to be upregulated in EAE microglia compared to phosphate-buffered saline (PBS) treated mice. These genes are primarily involved in immune-related pathways, including Toll-like receptor (TLR) signaling, and interact with MS therapeutics such as teriflunomide. Among the identified DEcircRNAs, circGAS2 (mmu-circ-0001569) was significantly upregulated, suggesting its potential regulatory role in microglial function. The expression trends of these biomarkers were validated via quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis.
Conclusions:
This study provides a comprehensive microglial gene signature for EAE, highlighting the involvement of TLR pathways and circRNA-mediated regulation in MS pathogenesis. These findings provide a foundation for future research into microglia-targeted therapies and diagnostic tools for MS.
Insights
Researchers identified key microglial gene signatures in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis (MS) model. These findings reveal Toll-like receptor (TLR) pathway involvement and potential circRNA regulation in MS, paving the way for new therapies.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Genomics
Background:
- Multiple sclerosis (MS) is a chronic neuroinflammatory disease driven by immune dysregulation and demyelination.
- Microglia are central to MS pathogenesis, but their specific gene expression patterns in the disease remain unclear.
- Understanding microglial contributions is crucial for developing effective MS treatments.
Purpose of the Study:
- To identify and characterize microglial gene signatures associated with MS pathogenesis.
- To explore the role of differentially expressed RNAs (mRNAs, lncRNAs, circRNAs, miRNAs) in microglia during EAE.
- To investigate potential therapeutic targets by analyzing interactions with existing MS drugs.
Main Methods:
- Utilized an experimental autoimmune encephalomyelitis (EAE) mouse model.
- Performed RNA sequencing to identify differentially expressed RNAs in microglia.
- Applied machine learning for multigene signature selection, followed by pathway analysis (GO, KEGG) and qRT-PCR validation.
- Conducted molecular docking studies with MS therapeutics.
Main Results:
- Identified six key upregulated microglial mRNA biomarkers: NGP, HIST1H2BJ, PBLD1, MBNL3, CD180, and F10.
- These genes are involved in immune pathways, including Toll-like receptor (TLR) signaling, and show potential interactions with teriflunomide.
- Significantly upregulated circGAS2 was identified, suggesting a regulatory role in microglial function during EAE.
Conclusions:
- Established a comprehensive microglial gene signature for EAE, implicating TLR pathways and circRNA regulation in MS.
- The identified biomarkers and pathways offer a foundation for developing targeted MS therapies and diagnostics.
- Highlights the critical role of microglia in MS pathogenesis and potential avenues for therapeutic intervention.
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