Chopping GSDMD: caspase‐8 has joined the team of pyroptosis‐mediating caspases

Inflammatory and apoptotic caspases mediate two distinct forms of cell death: pyroptosis and apoptosis, respectively. Three independent studies have now demonstrated that the “apoptotic” caspase‐8 can cleave gasdermin D (GSDMD) leading to pyroptosis‐like cell death and IL‐1β release in murine macrophages (Orning et al , 2018; Sarhan et al , 2018; Chen et al , 2019). Orning et al and Chen/Demarco et al also show that the NLRP3 inflammasome is activated downstream of active caspase‐8, but they attribute this inflammasome activation to different pore‐forming proteins, GSDMD and pannexin‐1, respectively (Orning et al , 2018; Chen et al , 2019). Graphical Abstract While caspase‐8 is normally associated with apoptosis, recent studies show that it is also involved in pyroptosis, cleaving gasdermin D to trigger pyroptosis‐like cell death and IL‐1β release in macrophages.