Pyroptosis is a pro-inflammatory form of cell death that is driven by gasdermin (GSDM)-mediated membrane pore formation, which leads to secretion of inflammatory cytokines and cell rupture. Tight regulation of gasdermin activation and pore formation is crucial to prevent excessive pyroptosis, which can cause inflammatory diseases. In a study published in Cell, Wright, Kumari et al. reveal a mechanism for the intercellular spread of pyroptosis, which may exacerbate inflammation in vivo.

Pyroptosis spread from competent to naive cells without direct cell–cell contact; both compartmentalized transwell co-cultures and supernatant from pyroptotic cells induced bystander death, implicating a secreted factor in the propagation of pyroptosis. Fractionation of supernatant from pyroptotic cells identified extracellular vesicles (EVs) as this secreted factor. Isolated pyroptotic EVs caused lytic death in naive wild-type cells, whereas EV-depleted supernatant did not. Injection of pyroptotic EVs into GSDMD-mutant mice induced cell death and tissue damage concurrent with an upregulation of cell-death- and inflammation-linked pathways.