Review: the role of GSDMD in sepsis

Abstract

Purpose: Gasdermin D (GSDMD) is a cytoplasmic protein that is encoded by the gasdermin family GSDMD gene and is the ultimate executor of pyroptosis. Pyroptosis is a mode of lysis and inflammation that regulates cell death, ultimately leading to cell swelling and rupture. In sepsis, a dysregulated host response to infection frequently results in hyperinflammatory responses and immunosuppression, eventually leading to multiple organ dysfunction. Pyroptosis regulates innate immune defenses and plays an important role in the process of inflammatory cell death, and the absence of any link in the entire pathway from GSDMD to pyroptosis causes bacterial clearance to be hampered. Under normal conditions, the process of pyroptosis occurs much faster than apoptosis, and the threat to the body is also much greater.

Materials and methods: We conducted a systematic review of relevant reviews and experimental articles using the keywords sepsis, Gasdermin D, and Pyroptosis in the PubMed, Scopus, Google Scholar, and Web of Science databases.

Conclusion: Combined with the pathogenesis of sepsis, it is not difficult to find that pyroptosis plays a key role in bacterial inflammation and sepsis. Therefore, GSDMD inhibitors may be used as targeted drugs to treat sepsis by reducing the occurrence of pyroptosis. This review mainly discusses the key role of GSDMD in sepsis.

Keywords: Gasdermin D; Multiple organ dysfunction syndrome; Pyroptosis; Sepsis.

Fig. 1

An overview of the molecular mechanisms of pyroptosis. Pyroptosis is a type of cell death mediated by caspase-specific proteases (caspase-specific proteases). The canonical pathway of pyroptosis mainly depends on caspase-1. PAMPs and DAMPs associated molecular patterns in the cytoplasm can stimulate inflammasome assembly, leading to the processing and activation of caspase-1, which converts pro-IL-1β and pro-IL-18 cleavage to mature form and cleavage of gasdermin D. The non-canonical pathway of pyroptosis mainly depends on caspase-11 (the human homologous caspase-4/5), activation of caspase 11/4/5 does not normally require PRR-mediated inflammasome, caspase-11 can directly recognize LPS in the cytoplasm for oligomerization and activation, disrupt the membrane structure by cleaving and activating GSDMD. GSDMD has two conserved domains: an N-terminal effector domain and a C-terminal inhibitory domain. The N-terminal is the main functional domain and is involved in the occurrence of pyroptosis, while the C-terminal has an auto-inhibitory function. In the resting state, the N-terminal and C-terminal domains are connected by a long loop. When stimulated by an external signal, Caspase-1/4/5/11 activates the cleavage of GSDMD protein, and GSDMD-NT is activated to bind to the cell membrane. The phospholipid protein binds, multimerizes, and forms a hole in the cytoplasmic membrane, which damages the cytoplasmic membrane and induces the occurrence of pyroptosis. At the same time, activated forms of pro-inflammatory cytokines such as IL-1β and IL-18 are released through the hole, leading to a massive inflammatory response

Fig. 2

GSDMD dominates organ damage, cellular and molecular regulation in sepsis. During sepsis, bacteria enter the blood, neutrophils increase the release of pro-inflammatory factors, reactive oxygen species and HMGB1, and the body produces coagulation dysfunction, lung injury, myocardial injury, liver injury, and intestinal injury. GSDMD, which functions as a motor, is usually involved in the damage of these molecules and the body