MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells
Yun-Ji Lim,
Sang-A Park,
Dandan Wang,
Wenwen Jin,
Wai Lim Ku,
Dunfang Zhang,
Junji Xu,
Liliana C. Patiño,
Na Liu,
Weiwei Chen,
Rida Kazmi,
Keji Zhao,
Ying E. Zhang,
Lingyun Sun,
WanJun Chen
Affiliations
Yun-Ji Lim
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Sang-A Park
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Dandan Wang
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Wenwen Jin
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Wai Lim Ku
Systemic Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA
Dunfang Zhang
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Junji Xu
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Liliana C. Patiño
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Na Liu
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Weiwei Chen
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Rida Kazmi
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
Keji Zhao
Systemic Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA
Ying E. Zhang
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Lingyun Sun
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Corresponding author
WanJun Chen
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
