Gasdermin D plays a vital role in the generation of neutrophil extracellular traps

TLDR

Cell death normally occurs via apoptosis, but when homeostasis is disrupted it can shift to pro‑inflammatory forms such as necroptosis, pyroptosis, or NETosis, with gasdermin D acting as a pore‑forming executor of pyroptosis. The study demonstrates that gasdermin D is essential for neutrophil extracellular trap formation and proposes it as a key mediator of NETosis. During NETosis, gasdermin D is cleaved by neutrophil proteases, triggering a feed‑forward loop that promotes protease activation and nuclear expansion, and a pyrazolo‑oxazepine‑based small molecule was identified that blocks this process. The identified small‑molecule inhibitor effectively suppresses NET formation and gasdermin D‑mediated pyroptotic cell death in human cells.

Abstract

The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.