Cell death plays a central role in both homeostasis and human pathology. While apoptotic cells are orderly packed in ‘apoptotic bodies’ for uptake by neighboring cells and professional phagocytes, pyroptosis is a non-physiological lytic programmed cell death mode that results in spilling of the intracellular content in the extracellular environment. This lytic programmed cell death mode is increasingly associated with differential pathophysiological outcomes in (acute) infectious and (chronic) inflammatory diseases, respectively. Pyroptosis has been implicated in host defense against bacterial pathogens such as Francisella tularensis, Salmonella Typhimurium, Escherichia coli, Legionella pneumophila and Burkholderia thailandensis. Under conditions of chronic inflammation, however, pyroptosis may be detrimental to the host. This is best illustrated by the observation that genetic deletion of caspase-1 is significantly more effective in controlling early perinatal lethality and inflammatory pathology of Muckle Wells Syndrome-associated Nlrp3 knock-in mice relative to preventing downstream signaling through its inflammatory cytokine substrates interleukin (IL)-1β and IL-18. In addition, recent studies suggest that pyroptosis may be linked to macrophage activation syndrome in autoinflammatory patients with Nlrc4 mutations. A likely cause is that in addition to IL-1β and IL-18, pyroptotic cells release an amount of inflammatory mediators and danger signals (HMGB1, IL-1α, S100A8 and S100A9, heat-shock proteins, etc.) that may contribute importantly to destructive inflammatory responses in the context of chronic inflammatory disease. Once released into the extracellular space, these effectors can enhance inflammatory, cell survival and repair responses through activation of cell surface receptors such as the IL-1 and IL-18 receptors and the receptor for advanced glycation endproducts (RAGE). However, the cellular and biochemical mechanisms by which inflammatory caspases and the pore-forming protein GSDMD drive pyroptosis largely remain to be identified. Additionally, the in vivo role of pyroptosis in driving immune-related pathology and disease outcomes has not been established and it is unclear how inflammasomes can steer alternative cell death modes. Here, we aim to characterize the cell biological and molecular requirements of different inflammasome-induced cell death types, and to explore the therapeutic potential of inflammasome-driven cell death switching in chronic inflammatory diseases with high unmet medical need.
