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

Fei Han; Hao Chen; Lin Chen; Chenchen Yuan; Qinhao Shen; Guotao Lu; Weiwei Chen; Weijuan Gong; Yanbing Ding; Aidong Gu; Lide Tao

doi:10.1016/j.bbrc.2023.02.082

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

Biochem Biophys Res Commun. 2023 Apr 30:654:26-33. doi: 10.1016/j.bbrc.2023.02.082. Epub 2023 Mar 1.

Authors

Fei Han¹, Hao Chen², Lin Chen³, Chenchen Yuan³, Qinhao Shen³, Guotao Lu³, Weiwei Chen⁴, Weijuan Gong³, Yanbing Ding⁵, Aidong Gu⁶, Lide Tao⁷

Affiliations

¹ Dalian Medical University, Dalian, 116044, Liaoning, China; Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China; Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China.
² Dalian Medical University, Dalian, 116044, Liaoning, China; The First Affiliated Hospital of Dalian Medical University, Dalian, 116044, Liaoning, China.
³ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China; Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China.
⁴ Department of Gastroenterology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou University, Yangzhou, 225000, Jiangsu, China.
⁵ Dalian Medical University, Dalian, 116044, Liaoning, China; Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China; Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China. Electronic address: ybding@yzu.edu.cn.
⁶ Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, Jiangsu, China. Electronic address: xzgad@163.com.
⁷ Department of Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China. Electronic address: ldtao@yzu.edu.cn.

PMID: 36889032
DOI: 10.1016/j.bbrc.2023.02.082

Abstract

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.

Keywords: Acute pancreatitis; Gasdermin D; Neutrophil extracellular traps; Neutrophils.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Animals
Extracellular Traps* / metabolism
Gasdermins
Mice
Mice, Knockout
Neutrophils / metabolism
Pancreatitis* / metabolism
Pancreatitis* / prevention & control

Substances

Gasdermins