Does Pyroptosis Play a Role in Inflammasome-Related Disorders?

Abstract

Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1β, IL-1α, and IL-18 and induce a type of inflammatory cell death known as "pyroptosis". Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions.

Keywords: RCD; apoptosis; inflammasome disease; inflammasomes; necroptosis; pyroptosis.

Figure 1

Simplified model of apoptosis and necroptosis. FADD, FAS-associated death domain; RIPK1/3, receptor-interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like; TLRs, Toll-like receptors; ZBP1, Z-DNA-binding protein. Arrows indicate activation or facilitation.

Figure 2

Molecular features of pyroptosis. (1) Caspase-1-dependent pathway of pyroptosis; (2) caspase-4/-5/-11-dependent pathway of pyroptosis; (3) caspase-3-dependent pathway of pyroptosis; (4) caspase-1-independent pyroptosis selectively release IL-1α. PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; IL-1β, interleukin-1β; IL-18, interleukin-18; LPS, lipopolysaccharide; Panx1, Pannexin 1; GSDMD-N/C, N/C-terminal of gasdermin D; GSDME-N/C, N/C-terminal of gasdermin E; IAV, influenza A virus; ZBP, Z-DNA-binding protein 1; RIPK1/3, receptor-interacting protein kinase 1/3; NLRP3, NLR pyrin domain containing 3; FADD, FAS-associated death domain; Apaf-1, apoptotic protease activating factor-1; IL-1α, interleukin-1α. Red cross means the activated caspases cleave gasdermin D/E (GSDMD/E) at the junction of its N/C-terminal structural domains to produce gasdermin D/E N-terminal (NT) fragments; Arrows indicate activation or facilitation.

Figure 3

Inflammasomes and Inflammasome-related disorders association with pyroptosis. PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns; NLRP3, NLR pyrin domain containing 3; NLRC4, NLR containing a caspase recruitment domain 4; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; IL-1β, interleukin-1β; IL-18, interleukin-18; IL-1α, interleukin-1α. Arrows indicate activation or facilitation.