Pyroptotic

Pyroptotic is an adjective relating to pyroptosis, a form of programmed inflammatory cell death. Pyroptosis is characterized by rapid plasma membrane pore formation, cell swelling and lysis, and the release of pro-inflammatory intracellular contents. It is considered inflammatory in contrast to apoptosis, which is typically non-inflammatory. Pyroptosis is mediated by gasdermin family proteins, most prominently gasdermin D (GSDMD) in many contexts.

Mechanism: In many systems, pathogen- or danger-associated signals activate inflammasomes such as NLRP3, NLRC4, or AIM2, leading to activation of inflammatory caspases. In humans, this includes caspase-1 and, for noncanonical pathways, caspase-4 and caspase-5 (with caspase-11 serving the analogous role in mice). Caspase-1 cleaves GSDMD; the N-terminal fragment oligomerizes and forms membrane pores, driving cell lysis and the release of cytokines such as interleukin-1β and interleukin-18, which are also processed by caspase-1. In some contexts, caspase-3 can cleave GSDME (DFNA5), producing an N-terminal fragment that can execute a pyroptotic-like lytic death, potentially converting apoptosis into a pyroptotic phenotype.

Physiological and clinical relevance: Pyroptosis contributes to host defense against intracellular pathogens and shapes inflammatory responses through cytokine release. However, excessive pyroptosis or dysregulated inflammasome signaling is linked to inflammatory diseases, sepsis, and tissue injury. Therapeutic approaches are explored to modulate inflammasome activation, caspases, or gasdermins to mitigate harmful inflammation.

Terminology: The term pyroptotic describes cells or processes undergoing pyroptosis. It is part of the broader landscape of regulated cell death, alongside apoptosis, necroptosis, and ferroptosis.