Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis.

Pyoderma gangrenosum (PG) is characterized by the agonizing necrotizing ulcers with non-infectious neutrophil infiltration. Neutrophil extracellular traps (NETs) represent one of the mechanisms of neutrophils activation, and gasdermin D (GSDMD) plays a regulatory role in NETs. In this study, we discovered that the serum levels of NETs were elevated in PG patients compared to healthy controls. Injection of serum from PG patients into the dorsal skin of wild-type mice led to the formation of localized cutaneous ulcers. Furthermore, subsequent modeling demonstrated a significant increase of NETs and GSDMD in skin lesions and peripheral blood serum of wild-type mice. In GSDMD -/- mice, the severity of skin ulcers after modeling was significantly diminished. Overall, our findings shed light on the role of GSDMD in regulating the production of NETs by neutrophils and the release of inflammatory factors in the pathogenesis of PG and establish an animal model for studying PG.