Mir221/222 drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• MicroRNAs (miRNAs) regulate gene expression and are implicated in diseases like rheumatoid arthritis (RA).
• miRNA deregulation is observed in RA, but their specific function in synovial fibroblasts (SFs), key cells in arthritis, is not fully understood.
• Previous research indicates elevated miR221/222 expression in RA SFs.

Purpose of the Study:

• To investigate the specific role of miR221/222 in the pathogenesis of RA within synovial fibroblasts.
• To elucidate the molecular mechanisms by which miR221/222 influence SF behavior and contribute to arthritis development.

Main Methods:

• Murine SFs were treated with TNF, IL-1β, and IFN-γ to assess miR221/222 gene expression.
• SF-specific overexpression and ablation of miR221/222 were performed in huTNFtg mice.
• Transcriptional profiling and single-cell ATAC-seq were used to analyze SFs.
• Target validation for miR221/222 was conducted.

Main Results:

• TNF and IL-1β, but not IFN-γ, activated miR221/222 expression in murine SFs.
• SF-specific miR221/222 overexpression exacerbated arthritis and increased SF expansion in huTNFtg mice.
• Total ablation of miR221/222 reduced SF expansion and attenuated disease.
• miR221/222 overexpression altered SFs' transcriptional profile, affecting cell cycle and extracellular matrix regulation pathways.
• Validated targets included cell cycle inhibitors CDKN1B, CDKN1C, and epigenetic regulator SMARCA1.
• Single-cell ATAC-seq revealed increased miR221/222 activity in pathogenic SF subclusters, regulated by transcription factors like Rela, Relb, Junb, Bach1, and Nfe2l2.

Conclusions:

• miR221/222 play a significant, SF-specific pathogenic role in arthritis.
• Therapeutic targeting of miR221/222 in specific SF subpopulations could lead to novel, fibroblast-targeted therapies for RA.