Pyroptosis

Pyroptosis is a form of programmed cell death that is inherently inflammatory. It is driven by caspase activation and the action of gasdermin family proteins, leading to pore formation in the plasma membrane, cell swelling, membrane rupture, and the release of pro-inflammatory cytokines and danger signals. Unlike apoptosis, which is generally non-inflammatory, pyroptosis results in rapid recruitment of immune cells and amplification of inflammatory responses.

In the canonical pathway, inflammasomes activate inflammatory caspases, most notably caspase-1. Active caspase-1 processes pro-interleukin-1β and pro-interleukin-18 into their mature, secreted forms and cleaves gasdermin D (GSDMD). The N-terminal fragment of GSDMD oligomerizes to form membrane pores, causing ionic flux, water influx, cell swelling, and lytic cell death. This pathway also facilitates the release of cytokines and danger-associated molecular patterns (DAMPs) such as IL-1β, IL-18, and HMGB1.

A non-canonical pathway involves caspase-4 and caspase-5 in humans (caspase-11 in mice), which detect intracellular LPS from Gram-negative bacteria. These caspases cleave GSDMD directly, triggering pore formation and pyroptosis, which can subsequently activate the canonical inflammasome cascade and cytokine maturation.

Gasdermin D is the principal executor in most pyroptotic cells, though other gasdermins (for example GSDME) can mediate pyroptosis under certain conditions, linking apoptotic signaling to inflammatory cell death. Pyroptosis is implicated in host defense against pathogens but also contributes to tissue damage in infections, autoinflammatory diseases, and some cancers, making components of the pathway potential therapeutic targets.