Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma

Takehiro Takahashi, Yoshihide Asano, Koji Sugawara, Takashi Yamashita, Kouki Nakamura, Ryosuke Saigusa, Yohei Ichimura, Tetsuo Toyama, Takashi Taniguchi, Kaname Akamata, Shinji Noda, Ayumi Yoshizaki, Daisuke Tsuruta, Maria Trojanowska, Shinichi Sato

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1129-1151
Number of pages23
JournalJournal of Experimental Medicine
Volume214
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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