GATA6 promotes fibrotic repair of tracheal injury through NLRP3 inflammasome-mediated epithelial pyroptosis

作者全名："Li, Anmao; Gu, Lei; He, Chunyan; Li, Yishi; Peng, Mingyu; Liao, Jiaxin; Xiao, Rui; Xu, Li; Guo, Shuliang"

作者地址："[Li, Anmao; Gu, Lei; He, Chunyan; Li, Yishi; Peng, Mingyu; Liao, Jiaxin; Xiao, Rui; Xu, Li; Guo, Shuliang] Chongqing Med Univ, Affiliated Hosp 1, Dept Pulm & Crit Care Med, Chongqing, Peoples R China"

通信作者："Guo, SL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Pulm & Crit Care Med, Chongqing, Peoples R China."

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001052257900001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：123

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Tracheal injury; GATA6; NLRP3 inflammasome; Pyroptosis; NF; & kappa;B pathway

摘要："Tracheal injury is a challenging emergency condition that is characterized by the abnormal repair of the trachea. GATA6, a well-established transcription factor, plays a crucial role in tissue injury and epithelial regenerative repair. This study aims to evaluate the role of GATA6 in NF-?B-mediated NLRP3 inflammasome activation and pyroptosis after tracheal injury. Tracheal tissues and serum samples were collected from clinical patients and a rat model of tracheal injury. Upon GATA6 knockdown or overexpression, BEAS-2B and rat tracheal epithelial (RTE) cells were treated with lipopolysaccharides and nigericin before being co-cultured with primary tracheal fibroblasts. The changes of NLRP3 inflammasome activation and pyroptosis and their underlying mechanisms were detected. Additionally, the role of GATA6 downregulation in tracheal injury was verified in rats. GATA6 expression and NLRP3 inflammasome activation were upregulated following tracheal injury in the epithelium of granulation tissues. GATA6 silencing inhibited NLRP3 priming, NLRP3 inflammasome activation, and pyroptosis in BEAS-2B and RTE cells. Mechanistically, GATA6 was determined to have bound to the promoter region of NLRP3 and synergistically upregulated NLRP3 promoter activity with NF-?B. Furthermore, GATA6 overexpression promoted epithelial-mesenchymal transition via modulating the NF-?B/NLRP3 pathway. Epithelial NLRP3 inflammasome activation triggered ECM production in fibroblasts, which was suppressed by GATA6 knockdown and induced by GATA6 overexpression. Finally, the downregulation of GATA6 alleviated NLRP3 inflammasome-mediated pyroptosis induced by tracheal injury in rats, thereby reducing tracheal stenosis, inflammation, and fibrosis. GATA6 promotes fibrotic repair in tracheal injury through NLRP3 inflammasomemediated epithelial pyroptosis, making it a potential biological therapeutic target for tracheal injury."

基金机构：National Major Science and Technology Projects of China [2018ZX10302302003]; Chongqing young and middle-aged medical high-end talent studio-Lung Nodule Studio; Chongqing talents projects

基金资助正文："& nbsp;This work was funded by the National Major Science and Technology Projects of China (Grants 2018ZX10302302003) , Chongqing young and middle-aged medical high-end talent studio-Lung Nodule Studio, and Chongqing talents projects-Famous masters and teachers (Shuliang Guo) ."