1. Academic Validation
  2. Inhibition of STAT3 phosphorylation by colchicine regulates NLRP3 activation to alleviate sepsis-induced acute lung injury

Inhibition of STAT3 phosphorylation by colchicine regulates NLRP3 activation to alleviate sepsis-induced acute lung injury

  • Inflammopharmacology. 2023 Apr 28. doi: 10.1007/s10787-023-01199-9.
Yuanshui Liu 1 2 Hang Yang 1 Fei Zhu 1 Yanhong Ouyang 2 Pinhua Pan 3
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, People's Republic of China.
  • 2 Department of Emergency Medicine, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, Hainan, People's Republic of China.
  • 3 Department of Respiratory Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, People's Republic of China. pinhuapan668@csu.edu.cn.
Abstract

The pharmacotherapeutic mechanism of colchicine, a tricyclic, lipid-soluble alkaloid extracted from the plant of the Lily family Colchicum autumnale, has not been fully understood in diverse disorders, including sepsis-induced acute lung injury (ALI). The study aimed at exploring the impact of colchicine on sepsis-induced ALI and the relevant mechanisms. Colchicine significantly attenuated ALI in mice caused by sepsis by alleviating respiratory dysfunction and pulmonary edema in mice, inhibiting NLRP3 inflammasome formation, and reducing oxidative stress, Pyroptosis, and Apoptosis of murine alveolar macrophage (J774A.1) cells. The targets of colchicine were predicted in the superPRED database and intersected with the differentially expressed genes in the GSE5883 and GSE129775 datasets. The major targets were subjected to protein-protein interaction network generation and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. It was thus found that colchicine inhibited STAT3 phosphorylation but did not alter STAT3 total protein expression. Phosphorylated STAT3 recruited EP300 to form a complex to promote histone H3 acetylation and histone H4 acetylation of NLRP3 promoter, leading to Pyroptosis of J774A.1 cells. In conclusion, inhibition of STAT3 phosphorylation by colchicine represses NLRP3 promoter acetylation via the STAT3/EP300 complex, thereby alleviating ALI caused by sepsis.

Keywords

Colchicine; EP300; NLRP3; STAT3; Sepsis-induced acute lung injury.

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