The circadian clock protein REVERBa inhibits pulmonary fibrosis development
The circadian clock protein REVERBa inhibits pulmonary fibrosis development
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生物钟蛋白 REVERBa 抑制肺纤维化发展
DOI：
10.1101/781666
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Cunningham P
中科院分区：
文献类型：
--
作者：
Cunningham P
肺部炎症反应受昼夜节律控制；然而，昼夜节律机制在潜在的纤维化表型中的重要性尚不清楚。在这里，我们发现了这些机制的显著变化，导致肺纤维化组织内振幅的增加和缺乏同步性。这些改变是间充质细胞浸润的结果，间充质细胞是肺纤维化发病机制中的一种重要细胞类型。在这些细胞中，核心时钟蛋白Reflbα的突变加剧了博莱霉素诱导的纤维化的发展，而在俱乐部或髓系细胞中的Reflbα突变对博莱霉素的表型没有影响。混响α的敲除揭示了鲜为人知的转录因子Tbpl1的调控。混响α和Tbpl1都改变了整合素β1局部黏附的形成，导致肌成纤维细胞活化增加。我们的发现的翻译重要性是通过对2个人类队列的分析而确定的。在英国生物库，昼夜节律紧张标记物(睡眠长度、时型和倒班工作)与肺纤维化有关，使其成为危险因素。在另一组研究中，人特发性肺纤维化肺组织中Reflbα的表达增加。药物靶向的混响α可抑制特发性肺间质纤维化患者成纤维细胞的肌成纤维细胞活化和器官培养的胶原分泌，提示靶向混响α可能是一种可行的治疗方法。
Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.