期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 4, 页码 1129-1151出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160247
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) [JP16H05366, JP25293242]
- Japan Intractable Diseases Research Foundation
- Rohto Dermatology Prize
- Japanese Society for Investigative Dermatology Fellowship Shiseido Award
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Takeda Science Foundation
- National Institutes of Health [AR042334]
- Grants-in-Aid for Scientific Research [16H06754, 15H06165, 16H05366, 17K16324] Funding Source: KAKEN
Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disorder characterized by vasculopathy and fibrosis in the skin and internal organs, most frequently in the esophagus and lungs. Hitherto, studies on SSc pathogenesis centered on immune cells, vascular cells, and fibroblasts. Although dysregulated keratinocytes in SSc have been recently reported, the contribution of epithelial cells to pathogenesis remains unexplored. In this study, we demonstrated the induction of SSc-like molecular phenotype in keratinocytes by gene silencing of transcription factor Friend leukemia virus integration 1 (Fli1), the deficiency of which is implicated in SSc pathogenesis. Keratin 14-expressing epithelial cell-specific Fli1 knockout mice spontaneously developed dermal and esophageal fibrosis with epithelial activation. Furthermore, they developed remarkable autoimmunity with interstitial lung disease derived from thymic defects with down-regulation of autoimmune regulator (Aire). Importantly, Fli1 directly regulated Aire expression in epithelial cells. Collectively, epithelial Fli1 deficiency might be involved in the systemic autoimmunity and selective organ fibrosis in SSc. This study uncovers unidentified roles of dysregulated epithelial cells in SSc pathogenesis.
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