Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma.
Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma.
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DOI：
10.1084/jem.20160247
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Sato S
中科院分区：
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作者：
Takahashi T;Asano Y;Sugawara K;Yamashita T;Nakamura K;Saigusa R;Ichimura Y;Toyama T;Taniguchi T;Akamata K;Noda S;Yoshizaki A;Tsuruta D;Trojanowska M;Sato S
Takahashi等人发现，小鼠中转录因子Fli1的上皮细胞条件性敲低驱动源自胸腺缺陷的全身性自身免疫以及皮肤和食管中的选择性组织纤维化，模拟人类硬皮病。这项研究解开了关于这种疾病中自身免疫和选择性组织纤维化起源的未回答的问题。系统性硬化症（SSc）或硬皮病是一种多系统自身免疫性疾病，其特征是皮肤和内脏器官的血管病变和纤维化，最常见于食道和肺。目前，对SSc发病机制的研究集中在免疫细胞、血管细胞和成纤维细胞。尽管最近有报道称SSc中角质形成细胞失调，但上皮细胞对发病机制的贡献仍未被探索。在这项研究中，我们证明了诱导角质形成细胞中的Ssc样分子表型的转录因子朋友白血病病毒整合1（Fli1），其中的缺陷是牵连在SSc的发病机制的基因沉默。表达角蛋白14的上皮细胞特异性Fli1基因敲除小鼠自发发生真皮和食管纤维化伴上皮活化。此外，他们发展了显着的自身免疫性与间质性肺疾病来源于胸腺缺陷与自身免疫调节因子（Aire）下调。重要的是，Fli1直接调节上皮细胞中的Aire表达。总之，上皮Fli1缺陷可能参与了SSc的系统性自身免疫和选择性器官纤维化。这项研究揭示了SSc发病机制中失调的上皮细胞的身份不明的作用。
Takahashi et al. find that epithelial cell–conditional knockdown of transcription factor Fli1 in mice drives systemic autoimmunity derived from thymic defects as well as selective tissue fibrosis in the skin and esophagus, mimicking human scleroderma. This study unravels the unanswered question about the origin of autoimmunity and selective tissue fibrosis in this disease. 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.