Inhibition of ER stress by targeting the IRE1α-TXNDC5 pathway alleviates crystalline silica-induced pulmonary fibrosis
Inhibition of ER stress by targeting the IRE1α-TXNDC5 pathway alleviates crystalline silica-induced pulmonary fibrosis
复制标题
通过靶向 IRE1 α-TXNDC5 通路抑制 ER 应激可减轻结晶二氧化硅诱导的肺纤维化
DOI：
10.1016/j.intimp.2021.107519
复制
发表时间：
2021-03-07
影响因子：
5.6
通讯作者：
Chen, Jie
中科院分区：
文献类型：
--
作者：
Chen, Xi;Li, Chao;Chen, Jie
长期接触结晶二氧化硅(CS)会导致矽肺，其特征是进行性肺纤维化。内质网在蛋白质加工过程中起着至关重要的作用，而外界刺激引起的未折叠蛋白质的积累往往会导致内质网应激。在目前的研究中，我们发现抑制内质网应激可以减轻CS诱导的肺纤维化。此外，我们观察到TXNDC5，一种驻留的ER蛋白，参与了成纤维细胞的激活。我们从机制上探讨了内质网应激与TXNDC5的关系，证明了IRE1α-XBP-1信号与TXNDC5密切相关。药物抑制IRE1α内切核糖核酸酶活性，除了下调XBP1的表达外，还可以减少激活的成纤维细胞中TXNDC5的表达。此外，体内药物抑制IRE1α可改善肺功能，延缓CS诱导的肺纤维化。综上所述，本研究阐明了内质网应激相关的IRE1α-TXNDC5信号在成纤维细胞激活中的作用及其在CS诱导的肺纤维化形成中的作用，这可能为矽肺的治疗提供新的靶点。
Long-term exposure to crystalline silica (CS) results in silicosis, which is characterized by progressive pulmonary fibrosis. The endoplasmic reticulum (ER) plays a critical role in protein processing, and the accumulation of unfolded proteins triggered by external stimuli often leads to ER stress. In the present study, we found that inhibition of ER stress alleviated CS-induced pulmonary fibrosis. Moreover, we observed that TXNDC5, a resident ER protein, was involved in the activation of fibroblasts. Mechanistically, we explored the relationship between ER stress and TXNDC5 and demonstrated that IRE1 alpha-XBP-1 signaling was closely related to TXNDC5. Pharmacological inhibition of IRE1 alpha endoribonuclease activity, in addition to knockdown of Xbp1 expression, reduced TXNDC5 expression in activated fibroblasts. Furthermore, pharmacological inhibition of IRE1 alpha in vivo ameliorated pulmonary function and delayed CS-induced lung fibrosis. In conclusion, the present study illuminates the role of ER stress-related IRE1 alpha-TXNDC5 signaling in fibroblast activation and its effects on CS-induced pulmonary fibrogenesis, which may provide novel targets for silicosis therapy.