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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\u2013expressing epithelial cell\u2013specific 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.<\/jats:p>","DOI":"10.1084\/jem.20160247","type":"journal-article","created":{"date-parts":[[2017,2,23]],"date-time":"2017-02-23T10:31:07Z","timestamp":1487845867000},"page":"1129-1151","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":82,"title":["Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma"],"prefix":"10.1084","volume":"214","author":[{"given":"Takehiro","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5560-9778","authenticated-orcid":true,"given":"Yoshihide","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-5692","authenticated-orcid":true,"given":"Takashi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Saigusa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Ichimura","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Toyama","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaname","family":"Akamata","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Yoshizaki","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Tsuruta","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Trojanowska","sequence":"additional","affiliation":[{"name":"Arthritis Center, Rheumatology, Boston University School of Medicine, Boston, MA 02118 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5519-172X","authenticated-orcid":true,"given":"Shinichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,2,23]]},"reference":[{"key":"2023072603545079200_bib1","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1038\/jid.2010.120","article-title":"Epithelial cells promote fibroblast activation via IL-1\u03b1 in systemic sclerosis","volume":"130","author":"Aden","year":"2010","journal-title":"J. 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