Mannan-Binding Lectin Reduces Epithelial-Mesenchymal Transition in Pulmonary Fibrosis via Inactivating the Store-Operated Calcium Entry Machinery.

IF 4.7 3区 医学 Q2 IMMUNOLOGY
Journal of Innate Immunity Pub Date : 2023-01-01 Epub Date: 2022-06-07 DOI:10.1159/000524693
Yunzhi Liu, Xianghuan Xie, Ping Wang, Jialiang Luo, Yu Chen, Qishan Xu, Jia Zhou, Xiao Lu, Jianbo Zhao, Zhengliang Chen, Daming Zuo
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引用次数: 2

Abstract

Idiopathic pulmonary fibrosis (IPF) is a type of idiopathic interstitial pneumonia with a poor clinical prognosis. Increasing evidence has demonstrated that epithelial-mesenchymal transition (EMT) contributes to the production of pathogenic myofibroblasts and plays a pivotal role in the development of pulmonary fibrosis. Mannan-binding lectin (MBL) is a soluble calcium-dependent complement molecule. Several studies have reported associations between serum MBL levels and lung diseases; however, the effect of MBL on IPF remains unknown. The present study observed aggravated pulmonary fibrosis in bleomycin-treated MBL-/- mice compared with their wild-type counterparts. Lung tissues from bleomycin-treated MBL-/- mice displayed a more severe EMT phenotype. In vitro studies determined that MBL inhibited the EMT process through attenuating store-operated calcium entry (SOCE) signaling. It was further demonstrated that MBL promoted the ubiquitination of Orai1, an essential component of SOCE, via pyruvate dehydrogenase kinase 1 (PDK1)-serum glucocorticoid-regulated kinase 1 signaling. PDK1 inhibition abolished the MBL-mediated regulation of SOCE activity and the EMT process. Notably, biochemical analysis showed that MBL interacted with PDK1 and contributed to PDK1 ubiquitination. In summary, the present findings suggested that MBL limited the EMT phenotype in human alveolar epithelial cells through regulation of SOCE, and MBL could be recognized as a potential therapeutic target for IPF.

甘露聚糖结合凝集素通过抑制储存操作的钙进入机制减少肺纤维化的上皮-间质转化。
特发性肺纤维化(IPF)是一种临床预后较差的特发性间质性肺炎。越来越多的证据表明,上皮-间充质转化(EMT)有助于产生致病性肌成纤维细胞,并在肺纤维化的发展中发挥关键作用。甘露聚糖结合凝集素(MBL)是一种可溶性钙依赖性补体分子。一些研究报告了血清MBL水平与肺部疾病之间的关系;然而,MBL对IPF的影响尚不清楚。本研究观察到博莱霉素处理的MBL-/-小鼠与野生型小鼠相比,肺纤维化加重。博来霉素处理的MBL-/-小鼠的肺组织表现出更严重的EMT表型。体外研究确定MBL通过减弱储存操作的钙进入(SOCE)信号来抑制EMT过程。进一步证明MBL通过丙酮酸脱氢酶激酶1(PDK1)-血清糖皮质激素调节激酶1信号传导促进SOCE的重要成分Orai1的泛素化。PDK1抑制消除了MBL介导的SOCE活性和EMT过程的调节。值得注意的是,生化分析表明MBL与PDK1相互作用,并有助于PDK1的泛素化。总之,目前的研究结果表明,MBL通过调节SOCE限制了人肺泡上皮细胞的EMT表型,MBL可以被认为是IPF的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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