The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.

Keywords: canonical pyroptosis pathway; caspase; non-canonical pyroptosis pathway; pyroptosis; sepsis.

Figure 1

The mechanism of canonical and non-canonical pyroptosis pathway. In the canonical pyroptosis pathway, intracellular pattern recognition receptors (e.g., NLRP1B, NLRP3, NLRC4, etc.) recognize the stimulus signals of pathogens and bind to pro-caspase-1 through the adaptor protein ASC to form a multi-protein complex that can activate caspase-1 protein. In the non-canonical pyroptosis pathway, intracellular LPS directly binds and activates caspase-11/4/5 protein to initiate pyroptosis. After inflammatory caspase activation, pro-IL-1β and pro-IL-18 are cleaved to active IL-1β and IL-18. The portion of GSDMD that connects the N- and C-terminals is rapidly cleaved to remove the inhibitory effect of the C-terminal on the N-terminal. Then, the N-terminal of GSDMD connects with phosphatidylinositol(PI) on the cell membrane, resulting in an oligomerization effect and formation of the “gasdermin channel”. Ion movement through this channel destroys the osmotic balance, leading to cell swelling, membrane dissolution, cell content release, and inflammatory response. Furthermore, cytosolic LPS stimulation induced caspase-11-dependent cleavage of the pannexin-1 channel followed by ATP release, which in turn activated the P2X7 receptor to cause ATP-induced loss of intracellular K+, NLRP3 inflammasome activation and IL-1b secretion.

Figure 2

The mechanism of new pyroptosis pathways. Activated by TNF-α or chemotherapy drugs, Caspase-3 cleavage and activate GSDME, releasing N-terminal binding to the cell membrane, forming “gasdermin channel” and inducing cell pyroptosis. Additionally, the pathogenic Yersinia could inhibit TAK1 via the effector YopJ, and then activated RIPK1 as well as Caspase-8, which would cleave GSDMD and GSDME, forming the “gasdermin channel” on the cell membrane, mediating pyroptosis and leading to the inflammatory response.