Pyroptosis-induced inflammation and tissue damage

Abstract

Pyroptosis is a programmed necrotic cell death executed by gasdermins, a family of pore-forming proteins. The cleavage of gasdermins by specific proteases enables their pore-forming activity. The activation of the prototype member of the gasdermin family, gasdermin D (GSDMD), is linked to innate immune monitoring by inflammasomes. Additional gasdermins such as GSDMA, GSDMB, GSDMC, and GSDME are activated by inflammasome-independent mechanisms. Pyroptosis is emerging as a key host defense strategy against pathogens. However, excessive pyroptosis causes cytokine storm and detrimental inflammation leading to tissue damage and organ dysfunction. Consequently, dysregulated pyroptotic responses contribute to the pathogenesis of various diseases, including sepsis, atherosclerosis, acute respiratory distress syndrome, and neurodegenerative disorders. This review will discuss the inflammatory consequences of pyroptosis and the mechanisms of pyroptosis-induced tissue damage and disease pathogenesis.

Keywords: Caspase-1; GSDMD; Inflammation; LPS; Pyroptosis; Sepsis.

Figure 1.. Inflammasome-mediated GSDMD activation and pyroptosis.

Caspase-1 activation by canonical inflammasome complexes or caspase-11-noncanonical inflammasome activation by cytosolic LPS initiates gasdermin-D (GSDMD) cleavage and membrane pore formation. K+ efflux through GSDMD pores also activates NLRP3 inflammasome and caspase-11, which cleaves pro-IL-1β and pro-IL-18 to active cytokines. Pro-inflammatory cytokines like IL-1β, IL-18 and smaller DMAPs/alarmins like ATP, IL-1α, and galectin-1 are released through GSDMD pores. Ca+ influx through GSDMD pores activates tissue factor (TF) and initiates the coagulation cascade. Cells finally undergoes pyroptotic lysis mediated by ninjurin-1 (NINJ-1). The terminal cell rupture facilitates release of larger DAMPs such as HMGB1, LDH and SQSTM1, which cannot pass through GSDMD pore.

Figure 2.. Inflammasome-independent activation of gasdermins and pyroptosis.

Inflammation-independent activation of GSDMA, GSDMB, GSDMC, and GSDME by SpeB, granzyme A, caspase-8, and caspase-3/granzyme B, respectively, also leads to plasma membrane perforation and pyroptosis.

Figure 3.. Inflammatory and pathological consequences of pyroptosis

GSDMD pore formation and pyroptosis lead to the release of proinflammatory cytokines, alarmins and DAMPs. These inflammatory molecules act on bystander cells and promote a proinflammatory response. Cell death and exacerbated inflammation can lead to disruption of endothelial barrier in blood vessels and vital organs such as lungs, resulting in leucocyte infiltration. GSDMD pore formation also activates the coagulation cascade and contributes to lethality due to disseminated intravascular coagulation. Pyroptosis in neutrophils and other cells triggers NETosis. Aberrant NETosis and improper NET and DAMP removal can further induce pyroptosis and tissue damage.