Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis - PubMed (original) (raw)

Review

Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis

Christian Stoess et al. Front Cell Dev Biol. 2023.

Erratum in

Abstract

In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.

Keywords: MASH; MASLD; gasdermins; liver; pyroptosis; steatohepatitis; steatotic liver disease.

Copyright © 2023 Stoess, Leszczynska, Kui and Feldstein.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1

FIGURE 1

Pathways of pyroptosis and gasdermin activation. (A) Canonical pathway: Upon detection of DAMPs and PAMPs, inflammasome sensor NLRP3 recruits adaptor protein ASC to mediate CARD–CARD interactions with the effector cysteine protease caspase- 1. Active caspase-1 cleaves GSDMD into its NT fragment (GSDMDNT) and its auto-inhibitory C-terminal fragment. GSDMDNT oligomerizes and forms membrane pores which induces pyroptotic cell death. Caspase-1 also cleaves pro-IL-1β and pro-IL-18 into their active forms, which are released through GSDMD pores. (B) Non-canonical pathway: Human caspases 4 and 5 and the murine orthologue caspase-11 are activated by direct and highly specific binding of intracellular LPS from Gram-negative bacteria. After binding LPS via the caspase-4/5/11 CARD domain, a complex, called the non-canonical inflammasome, is formed without NLRs or ASC. Pyroptosis is induced by the ability of the caspase-11 inflammasome to directly cleave GSDMD into pore-forming GSDMDNT. Proteolysis of pro-IL-1β and pro-IL-18 requires active caspase-1 which can be triggered by K+ efflux. (C) Inflammasome-independent pathways of pyroptosis: Different proteins and enzymes have been discovered that control gasdermins and pyroptosis. Control over GSDMD and GSDME via non-inflammatory caspases indicates overlapping cell death pathways and control mechanisms.

FIGURE 2

FIGURE 2

Pyroptosis in MASH. Upon MASLD-associated metabolic and inflammatory changes, hepatocytes are constantly exposed to an increased concentration of free fatty acids (FFAs), DAMPs, and PAMPs, eventually triggering cell death, in particular pyroptosis. The release of intracellular DAMPs, such as mitochondria, host RNA and DNA, NLRP3 components, and mature IL-1β and IL-18, further induces pyroptosis in neighboring hepatocytes and nonparenchymal cells. IL-1β and IL-18 can selectively stimulate the transdifferentiation of quiescent HSCs to collagen-producing myofibroblasts. The uptake of extracellular NLRP3 components can also activate HSCs and facilitate fibrotic changes in the liver (Gaul et al., 2021). Activated HSCs transdifferentiate to myofibroblasts which promotes fibrogenesis and further maturation of proinflammatory interleukins, perpetuating the detrimental effects of cell death and inflammation. In resident macrophages (Kupffer cells, KCs) the imbalance of lipid homeostasis contributes to a proinflammatory polarization and enhances inflammation in MASLD. In addition, the extracellular DAMPs of stressed and dying hepatocytes perpetuate hepatic inflammation by stimulating KCs to secrete multiple proinflammatory and immune cell attracting cytokines (e.g. CCL2, CXCL10). Ultimately, this interplay leads to the infiltration of various subsets of immune cells, which can either exacerbate or resolve the condition of MASH.

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