title: Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma.
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-specificFli1knockout 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.
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan yasano-tky@umin.ac.jp.
authors.forename: Yoshihide
authors.identifier: 0000-0001-5560-9778
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.identifier: 0000-0002-4740-5692
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Saigusa
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Akamata
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Noda
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshizaki
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuruta
authors.affiliation: Arthritis Center, Rheumatology, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinichi
authors.identifier: 0000-0001-5519-172X
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D015551:Autoimmunity; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology; D004947:Esophagus / Q000473:pathology; D005355:Fibrosis; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D053547:Keratin-14 / Q000032:analysis; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000209:etiology*; D012867:Skin / Q000473:pathology; D058504:Th17 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D059467:Transcriptome; D000096927:AIRE Protein
chemical_list: D018398:Homeodomain Proteins; D053547:Keratin-14; D051789:Proto-Oncogene Protein c-fli-1; D014157:Transcription Factors; D000096927:AIRE Protein; C078433:FLI1 protein, human; C497426:Fli1 protein, mouse; C064658:RAG-1 protein