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Review
. 2018 Mar 7:2018:5823823.
doi: 10.1155/2018/5823823. eCollection 2018.

Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

Yu-Lei Gao  1 , Jian-Hua Zhai  1 , Yan-Fen Chai  1
Affiliations
Review

Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

Yu-Lei Gao et al. Mediators Inflamm. .

Abstract

Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words "pyro" and "ptosis" in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. 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. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.

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Figures

Figure 1
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.
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