Inhibition of Gasdermin D blocks the formation of NETs and protects acute pancreatitis in mice

• Published in: Biochemical and biophysical research communications Vol. 654; pp. 26 - 33
• Main Authors: Han, Fei, Chen, Hao, Chen, Lin, Yuan, Chenchen, Shen, Qinhao, Lu, Guotao, Chen, Weiwei, Gong, Weijuan, Ding, Yanbing, Gu, Aidong, Tao, Lide
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2023
• Subjects: Acute Disease; Acute pancreatitis; Animals; Extracellular Traps - metabolism; Gasdermin D; Gasdermins; Mice; Mice, Knockout; Neutrophil extracellular traps; Neutrophils; Neutrophils - metabolism; Pancreatitis - metabolism; Pancreatitis - prevention & control; Gasdermin D; Acute pancreatitis; Neutrophil extracellular traps; Neutrophils
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.02.082

The persistent activation of neutrophils and the excessive neutrophil extracellular traps (NETs) formation are the main determinants of pancreatic tissue injury and systemic inflammatory response in acute pancreatitis (AP). Thus, inhibiting the release of NETs can effectively prevent the aggravation of AP. Here, our study showed that the pore-forming protein gasdermin D (GSDMD) was activity in neutrophils of AP mice and patients and played the vital role in NETs formation. Through the application of GSDMD inhibitor or the construction of neutrophil GSDMD specific knockout mice, it was found in vivo and in vitro that inhibition of GSDMD could block the NETs formation, reduce pancreatic injury, systemic inflammatory reaction and organ failure in AP mice. To sum up, our findings confirmed that neutrophil GSDMD was the therapeutic target for improving the occurrence and development of AP. •GSDMD was activity in neutrophils of AP patients.•Both genetic knockout and drug-induced inhibition of GSDMD inhibited the formation of NETs in vitro.•Neutrophil GSDMD specific knockout alleviated the AP model in mice, reduced pancreatic injury, systemic inflammatory reaction in AP mice.•GSDMD targeting neutrophils may be expected to become one of the potential targets for the treatment of AP in future clinical work.