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

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 in-hibitor 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 inflam-matory 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.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

The persistent activation of neutrophils and excessive neutrophil extracellular traps (NETs) formation are the main factors causing pancreatic tissue injury and systemic inflammatory response in acute pancreatitis (AP). Inhibiting the release of NETs can effectively prevent the worsening of AP. This study found that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils of AP mice and patients and plays a crucial role in NETs formation. Inhibition of GSDMD was shown to block NETs formation, reduce pancreatic injury, systemic inflammatory reaction, and organ failure in AP mice. Therefore, neutrophil GSDMD is identified as a therapeutic target for improving the occurrence and development of AP.