Pyroptosis

Pyroptosis is a highly inflammatory form of programmed cell death executed primarily by gasdermin family proteins, especially gasdermin D (GSDMD), which oligomerise to form pores in the plasma membrane after cleavage by inflammatory caspases (caspase-1, -4, -5 in humans; caspase-11 in mice). In the canonical pathway, caspase-1 directly cleaves both GSDMD and pro-IL-1β and pro-IL-18 into their mature secreted forms; in the non-canonical pathway, caspase-4/-5/-11 cleave GSDMD to form pores, while IL-1β and IL-18 maturation requires secondary NLRP3/caspase-1 activation triggered by potassium efflux through the GSDMD pores. Pyroptosis is triggered downstream of inflammasome complexes, including the NLRP3 inflammasome, in response to pathogen-associated molecular patterns, damaged-self signals and sterile stressors. In the context of ageing and age-related disease, dysregulated pyroptosis contributes to tissue inflammation in conditions including atherosclerosis, neurodegeneration and metabolic disease.