Loss of ELK1 has differential effects on age-dependent organ fibrosis.
Loss of ELK1 has differential effects on age-dependent organ fibrosis.
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DOI：
10.1016/j.biocel.2019.105668
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发表时间：
2020-03
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影响因子：
--
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--
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ETS 结构域蛋白 1 (ELK1) 是一种转录抑制因子，对于调节 αvβ6 整合素表达非常重要。 αvβ6 整合素激活促纤维化细胞因子转化生长因子 β1 (TGFβ1)，并在特发性肺纤维化 (IPF) 的肺泡上皮细胞中增加。 IPF 是一种与衰老相关的疾病，因此我们假设全球缺乏 Elk1 的老年动物会在与 avb6 介导的 TGFb 激活有关的器官中发生自发纤维化。在这里，我们发现，一岁以下的 Elk1 敲除 (Elk1−/0) 小鼠在肺和肝脏没有损伤的情况下出现自发性纤维化，但心脏或肾脏没有损伤。 Elk1−/0 老年小鼠的肺部表现出胶原蛋白沉积增加，特别是胶原蛋白 3α1，位于小纤维化病灶和增厚的肺泡壁中。尽管肝脏的 ELK1 表达水平相对较低，但 Elk1−/0 动物仍出现肝脂肪变性和纤维化。 Elk1 的缺失还对四个器官中的 Itgb1、Itgb5 和 Itgb6 基因表达产生不同的影响，这可能解释了这些器官的表型差异。了解人类疾病中 ELK1 减少的潜在原因最后，我们将人类细胞和小鼠肺切片暴露于香烟烟雾提取物中，导致 ELK1 表达减少，这可能解释了人类疾病中 ELK1 的缺失。这些数据支持 ELK1 通过 β 整联蛋白亚基基因的转录调节来防止进行性纤维化的发展，并证明 ELK1 的丢失可能是由香烟烟雾引起的。
ETS domain-containing protein-1 (ELK1) is a transcriptional repressor important in regulating αvβ6 integrin expression. αvβ6 integrins activate the profibrotic cytokine Transforming Growth Factor β1 (TGFβ1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where avb6 mediated TGFb activation has been implicated. Here we identify that Elk1-knockout (Elk1−/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1−/0 aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1−/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 genes expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1in human disease Finally we exposed human cells and murine lung slices to cigarette smoke extract which lead to reduced ELK1 expression which may explain the loss of ELK1 in human disease. These data support a fundament role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.
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影响因子：
17.1
作者：
Reed NI;Jo H;Chen C;Tsujino K;Arnold TD;DeGrado WF;Sheppard D
通讯作者：
Sheppard D
影响因子：
8
作者：
Naikawadi, Ram P.;Disayabutr, Supparerk;Wolters, Paul J.
通讯作者：
Wolters, Paul J.
影响因子：
6
作者：
Ma, LJ;Yang, HC;Fogo, AB
通讯作者：
Fogo, AB
影响因子：
16.6
作者：
Murray IR;Gonzalez ZN;Baily J;Dobie R;Wallace RJ;Mackinnon AC;Smith JR;Greenhalgh SN;Thompson AI;Conroy KP;Griggs DW;Ruminski PG;Gray GA;Singh M;Campbell MA;Kendall TJ;Dai J;Li Y;Iredale JP;Simpson H;Huard J;Péault B;Henderson NC
通讯作者：
Henderson NC
影响因子：
5.3
作者：
Chung, KC;Gomes, I;Rosner, MR
通讯作者：
Rosner, MR