Molecular pathway

Pyroptosis is initiated by the activation of canonical and non-canonical inflammasomes (Figure 3).

Non-canonical inflammasome pathway

In the non-canonical inflammasome pathway, lipopolysaccharides from gram-negative bacteria bind caspase 11 in mice, or caspases 4 and 5 in humans directly through their caspase activation and recruitment domains (CARDs). This induces caspase oligomerization and activation.

Canonical inflammasome pathway

Sensor proteins including Nod-like receptors (NLRs) detect pathogens and inflammatory agents. Pyroptosis triggered by activation of NLRC4 is the most extensively studied, although NLRC4 and NLRP1 inflammasomes can also trigger pyroptosis.

After activation, NLRC4 recruits the apoptosis-associated speck-like proteins containing CARD (ASC) adaptor protein. This complex dimerizes and activates caspase 1. Gasdermin cleavage

Once caspases 1, 11, 4 or 5 have been activated by either the canonical or non-canonical inflammasome pathway, they trigger pyroptosis by cleaving gasdermin D between Asp276 and Gly277^17–19. The resulting N terminal fragment is capable of inducing pyroptosis, whereas the C terminal fragment provides autoinhibition of gasdermin D.

Downstream events

Ultimately, pyroptosis initiation results in membrane pore formation, cell swelling followed by rupture. Events downstream of gasdermin D leads are currently unclear, although there is evidence that the N terminal fragment of gasdermin D oligomerizes in membranes to form pores¹⁹.

Figure 3 . Initiation of pyroptosis by canonical and non-canonical inflammasome pathways.