Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

Figure 1

Pyroptosis and sepsis. Pore-forming activity of GSDMD determines pyroptotic cell death. Direct binding of LPS to the protein procaspase-11 causes the protein dimerization to become active caspase-11. In human cells, caspase-4 and caspase-5 performed the function of mouse caspase-11. These caspases cleaved the protein GSDMD. The cytotoxic N-terminal fragment of GSDMD was then released and targets phospholipids on the host cell membrane. The NLRP 3 pathway is triggered by LPS molecules in the cytoplasm of infected cells. The inflammasome sensors recruit procaspase-1 monomers through the adaptor protein ASC and activate the caspase by dimerization. Caspase-1 can also initiate pyroptosis by cleaving gasdermin D although other pyroptosis-inducing caspase-1 substrates may exist. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection.