Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
| Autor: | Takehiro Takahashi, Yoshihide Asano, Shinji Noda, Daisuke Tsuruta, Kouki Nakamura, Ryosuke Saigusa, Maria Trojanowska, Koji Sugawara, Takashi Taniguchi, Tetsuo Toyama, Yohei Ichimura, Ayumi Yoshizaki, Kaname Akamata, Takashi Yamashita, Shinichi Sato |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Keratinocytes
0301 basic medicine Immunology Autoimmunity medicine.disease_cause Systemic scleroderma Scleroderma Pathogenesis Mice 03 medical and health sciences Esophagus Th2 Cells Immune system Fibrosis Animals Humans Immunology and Allergy Medicine skin and connective tissue diseases Skin Homeodomain Proteins Scleroderma Systemic integumentary system Proto-Oncogene Protein c-fli-1 business.industry Keratin-14 Epithelial Cells Autoimmune regulator medicine.disease 3. Good health Disease Models Animal 030104 developmental biology FLI1 Cancer research Th17 Cells Transcriptome business Transcription Factors |
| Zdroj: | Journal of Experimental Medicine. 214:1129-1151 |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|