NLRP3 inflammasome activation in alveolar epithelial cells promotes myofibroblast differentiation of lung-resident mesenchymal stem cells during pulmonary fibrogenesis

被引：37
作者：
Ji, Jie [1 ,2 ,4 ]
Hou, Jiwei [1 ,2 ,4 ]
Xia, Yunhui [1 ,2 ,4 ]
Xiang, Zou [3 ]
Han, Xiaodong [1 ,2 ,4 ]
机构：
[1] Nanjing Univ, Med Sch, Immunol & Reprod Biol Lab, Hankou Rd 22, Nanjing 210093, Peoples R China
[2] Nanjing Univ, Jiangsu Key Lab Mol Med, Nanjing 210093, Peoples R China
[3] Hong Kong Polytech Univ, Fac Hlth & Social Sci, Dept Hlth Technol & Informat, Hung Hom,Kowloon, Hong Kong, Peoples R China
[4] Nanjing Univ, Med Sch, State Key Lab Analyt Chem Life Sci, Nanjing 210093, Peoples R China
来源：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2021年 / 1867卷 / 05期
基金：
中国国家自然科学基金;
关键词：
Alveolar epithelial cell (AEC) dysfunction; Dickkopf-1 (DKK1); Lung-resident mesenchymal stem cells (LR-MSCs); NLRP3; inflammasome; Pulmonary fibrosis; Wnt/beta-catenin;
D O I：
10.1016/j.bbadis.2021.166077
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Idiopathic pulmonary fibrosis (IPF) is a lethal and agnogenic interstitial lung disease, which has limited therapeutic options. Recently, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome has been demonstrated as an important contributor to various fibrotic diseases following its persistent activation. However, the role of NLRP3 inflammasome in pulmonary fibrogenesis still needs to be further clarified. Here, we found that the activation of the NLRP3 inflammasome was raised in fibrotic lungs. In addition, the NLRP3 inflammasome was found to be activated in alveolar epithelial cells (AECs) in the lung tissue of both IPF patients and pulmonary fibrosis mouse models. Further research revealed that epithelial cells, following activation of the NLRP3 inflammasome, could induce the myofibroblast differentiation of lung-resident mesenchymal stem cells (LR-MSCs). In addition, inhibiting the activation of the NLRP3 inflammasome in epithelial cells promoted the expression of dickkopf-1 (DKK1), a secreted Wnt antagonist. DKK1 was capable of suppressing the profibrogenic differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis. In conclusion, this study not only provides a further in-depth understanding of the pathogenesis of pulmonary fibrosis, but also reveals a potential therapeutic strategy for disorders associated with pulmonary fibrosis.
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页数：11
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