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MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells
Yun-Ji Lim1, Sang-A Park1, Dandan Wang2
1Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA.
Abstract:
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-β) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-β-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.
Insights
MicroRNA-19b promotes T helper 9 cells, worsening systemic sclerosis (SSc). Inhibiting miR-19b ameliorates SSc in mice, suggesting a therapeutic target for this autoimmune disease.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- Systemic sclerosis (SSc) is a complex autoimmune disorder marked by widespread fibrosis.
- The precise immunological mechanisms driving SSc pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the role of microRNA-19b (miR-19b) in the development and progression of SSc.
- To elucidate the molecular pathways through which miR-19b influences T helper 9 (Th9) cell activity in SSc.
Main Methods:
- Utilized a bleomycin-induced mouse model of SSc.
- Analyzed CD4+ T cells for miR-19b and IL-9 expression.
- Investigated the molecular mechanisms involving TGF-β, IL-4, NLRC3, TRAF6, TAK1, NF-κB, and E2f8.
- Correlated miR-19b and IL-9 levels with disease severity in SSc patients.
Main Results:
- miR-19b and IL-9 levels are elevated in CD4+ T cells in experimental SSc.
- Inhibition of miR-19b reduced Th9 cells and ameliorated SSc symptoms in mice.
- A molecular pathway involving TGF-β, IL-4, NLRC3, TRAF6, TAK1, and NF-κB was identified, leading to miR-19b upregulation.
- miR-19b directly upregulates IL-9 by suppressing E2f8.
- Increased IL-9 and MIR-19B levels in SSc patients correlate with disease severity.
Conclusions:
- miR-19b is a critical mediator in Th9 cell-driven SSc pathogenesis.
- Targeting miR-19b presents a potential therapeutic strategy for managing SSc.
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