2. Academic Validation
  3. GATA6 promotes fibrotic repair of tracheal injury through NLRP3 inflammasome-mediated epithelial pyroptosis

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

  • Int Immunopharmacol. 2023 Jul 31;123:110657. doi: 10.1016/j.intimp.2023.110657.
Anmao Li 1,  Lei Gu 1,  Chunyan He 1,  Yishi Li 1,  Mingyu Peng 1,  Jiaxin Liao 1,  Rui Xiao 1,  Li Xu 1,  Shuliang Guo 2
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 37531826 DOI: 10.1016/j.intimp.2023.110657
Abstract

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-κB-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-κB. Furthermore, GATA6 overexpression promoted epithelial-mesenchymal transition via modulating the NF-κB/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 inflammasome-mediated epithelial Pyroptosis, making it a potential biological therapeutic target for tracheal injury.

Keywords

GATA6; NF-κB pathway; NLRP3 inflammasome; Pyroptosis; Tracheal injury.

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