Pyroptosis

Pyroptosis is considered an inflammatory cell death pathway that can be triggered by caspase‐1 or caspase‐11, or the human caspase‐11 orthologs, caspase‐4 and caspase‐5. The activation of caspase‐1 is mediated by supramolecular cytosolic protein complexes, termed inflammasomes, which sense specific pathogen, host or environmental danger molecules. Prior to causing pyroptotic death, caspase‐1 can also cleave and thereby activate the potent pro‐inflammatory cytokines, interleukin‐1 (IL‐1 ) and IL‐18. In contrast, the activation of caspase‐11 is caused by its direct binding to cytosolic lipopolysaccharide (LPS) derived from gram‐negative bacteria. While caspase‐11 can promote caspase‐1 activity, caspase‐1 is not required for caspase‐11 killing, and caspase‐11 itself does not efficiently activate IL‐1 or IL‐18. Unlike apoptotic caspase dependent cell death, caspase‐1 and caspase‐11 activation causes rapid cell swelling and the lytic rupture of the plasma membrane through an undefined mechanism. Pyroptosis can thereby result in the release of host damage associated molecular patterns (DAMPs), such as high‐mobility group protein B1 (HMGB1), into the external environment to induce inflammatory responses. Recent studies highlight that microbial activation of pyroptosis may also be an important host response designed to expose intracellular pathogens to the immune system. As such, pyroptotic driven release of DAMPs, the direct activation of pro‐inflammatory cytokines by caspase‐1, and the act of pyroptotic cell death itself, may all play important roles in host pathogen resistance or inflammation‐driven wound healing. On the other hand, pyroptotic cell death could also function in an anti‐inflammatory capacity by turning off a cells capability for producing active IL‐1 and IL‐18, although direct experimental evidence for this idea is limited. In this chapter we discuss how different pyroptotic stimuli are sensed, and the physiological roles for pyroptosis in promoting human health, or in contributing to auto‐inflammatory conditions such as septic shock. We also outline srecent evidence suggesting significant cross‐talk between pyroptotic, apoptotic and necroptotic cell death signaling pathways, and how this might have evolved to counteract microbial inhibition of host cell death and inflammatory signaling.