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

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. Alth...

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Autores principales: Takahashi, Takehiro, Asano, Yoshihide, Sugawara, Koji, Yamashita, Takashi, Nakamura, Kouki, Saigusa, Ryosuke, Ichimura, Yohei, Toyama, Tetsuo, Taniguchi, Takashi, Akamata, Kaname, Noda, Shinji, Yoshizaki, Ayumi, Tsuruta, Daisuke, Trojanowska, Maria, Sato, Shinichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379967/
https://www.ncbi.nlm.nih.gov/pubmed/28232470
http://dx.doi.org/10.1084/jem.20160247
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author Takahashi, Takehiro
Asano, Yoshihide
Sugawara, Koji
Yamashita, Takashi
Nakamura, Kouki
Saigusa, Ryosuke
Ichimura, Yohei
Toyama, Tetsuo
Taniguchi, Takashi
Akamata, Kaname
Noda, Shinji
Yoshizaki, Ayumi
Tsuruta, Daisuke
Trojanowska, Maria
Sato, Shinichi
author_facet Takahashi, Takehiro
Asano, Yoshihide
Sugawara, Koji
Yamashita, Takashi
Nakamura, Kouki
Saigusa, Ryosuke
Ichimura, Yohei
Toyama, Tetsuo
Taniguchi, Takashi
Akamata, Kaname
Noda, Shinji
Yoshizaki, Ayumi
Tsuruta, Daisuke
Trojanowska, Maria
Sato, Shinichi
author_sort Takahashi, Takehiro
collection PubMed
description 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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spelling pubmed-53799672017-10-03 Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma Takahashi, Takehiro Asano, Yoshihide Sugawara, Koji Yamashita, Takashi Nakamura, Kouki Saigusa, Ryosuke Ichimura, Yohei Toyama, Tetsuo Taniguchi, Takashi Akamata, Kaname Noda, Shinji Yoshizaki, Ayumi Tsuruta, Daisuke Trojanowska, Maria Sato, Shinichi J Exp Med Research Articles 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. The Rockefeller University Press 2017-04-03 /pmc/articles/PMC5379967/ /pubmed/28232470 http://dx.doi.org/10.1084/jem.20160247 Text en © 2017 Takahashi et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Takahashi, Takehiro
Asano, Yoshihide
Sugawara, Koji
Yamashita, Takashi
Nakamura, Kouki
Saigusa, Ryosuke
Ichimura, Yohei
Toyama, Tetsuo
Taniguchi, Takashi
Akamata, Kaname
Noda, Shinji
Yoshizaki, Ayumi
Tsuruta, Daisuke
Trojanowska, Maria
Sato, Shinichi
Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title_full Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title_fullStr Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title_full_unstemmed Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title_short Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma
title_sort epithelial fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379967/
https://www.ncbi.nlm.nih.gov/pubmed/28232470
http://dx.doi.org/10.1084/jem.20160247
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