Molecular Characteristics of Cell Pyroptosis and Its Inhibitors: A Review of Activation, Regulation, and Inhibitors

Wei, Shaoqiang; Feng, Min; Zhang, Shidong

doi:10.3390/ijms232416115

Cited by 13 publications

(6 citation statements)

References 154 publications

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“…GSDMD is a highly sought-after drug target, although the development of specific GSDMD inhibitors was not successful to date [44][45][46][47] . Therapeutic application of the potent pyroptosisinhibiting nanobodies described in this study would require efficient delivery of nanobodies into the cytosol of target cells.…”

Section: Recombinant Antagonistic Gsdmd Nanobodies Inhibit Pyroptosis...mentioning

confidence: 99%

Antagonistic nanobodies reveal mechanism of GSDMD pore formation and unexpected therapeutic potential

Schiffelers

Normann

BINDER

et al. 2023

Preprint

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Activation of various inflammasomes converges on the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases, followed by oligomerization of the N-terminal domain (GSDMDNT) and the assembly of pores penetrating target membranes. Yet, it remained unclear what triggers the conformational changes that allow membrane insertion, as methods to study pore formation in living cells were limited. We raised nanobodies specific for human GSDMD and found two nanobodies that prevent pyroptosis and IL-1β release when expressed in the cytosol of human macrophages. Nanobody binding to GSDMDNTblocked its oligomerization, while inflammasome assembly and GSDMD processing itself were not affected. The nanobody-stabilized monomers of GSDMDNTpartitioned into the plasma membrane, suggesting that pore formation is initiated by insertion of monomers, followed by oligomerization in the target membrane. When GSDMD pore formation was inhibited, cells still underwent caspase-1-dependent apoptosis, likely due to the substantially augmented caspase-1 activity. This hints at a novel layer of regulation of caspase-1 activity by GSDMD pores. Moreover, we revealed the unexpected therapeutic potential of antagonistic GSDMD nanobodies, as recombinant nanobodies added to the medium prevented cell death by pyroptosis, likely by entering through GSDMD pores and curtailing the assembly of additional pores. GSDMD nanobodies may thus be suitable to treat the ever-growing list of diseases caused by activation of the (non-) canonical inflammasomes.

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Section: Recombinant Antagonistic Gsdmd Nanobodies Inhibit Pyroptosis...mentioning

confidence: 99%

Antagonistic nanobodies reveal mechanism of GSDMD pore formation and unexpected therapeutic potential

Schiffelers

Normann

BINDER

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…It has two signaling pathways: a canonical pathway mediated by cysteine-1 and a non-canonical pathway mediated by cysteine-11 (Rühl et al, 2018). It is characterized by the activation of inflammatory cysteine-1 enzymes and cleavage of various members of the gasdermin family to form membrane-perforating, leading to cell membrane rupture, the release of inflammatory mediators and cell death ultimately (Wei et al, 2022). Autophagy refers to the catabolic process by which a cell turns over its own components (Yang and Klionsky, 2010).…”

Section: The Regulation Of Noncoding Rnas In Osteoporosismentioning

confidence: 99%

Noncoding RNAs: the crucial role of programmed cell death in osteoporosis

Han,

Zhu,

Zhang

et al. 2024

Front. Cell Dev. Biol.

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Osteoporosis is the most common skeletal disease characterized by an imbalance between bone resorption and bone remodeling. Osteoporosis can lead to bone loss and bone microstructural deterioration. This increases the risk of bone fragility and fracture, severely reducing patients’ mobility and quality of life. However, the specific molecular mechanisms involved in the development of osteoporosis remain unclear. Increasing evidence suggests that multiple noncoding RNAs show differential expression in the osteoporosis state. Meanwhile, noncoding RNAs have been associated with an increased risk of osteoporosis and fracture. Noncoding RNAs are an important class of factors at the level of gene regulation and are mainly involved in cell proliferation, cell differentiation, and cell death. Programmed cell death is a genetically-regulated form of cell death involved in regulating the homeostasis of the internal environment. Noncoding RNA plays an important role in the programmed cell death process. The exploration of the noncoding RNA-programmed cell death axis has become an interesting area of research and has been shown to play a role in many diseases such as osteoporosis. In this review, we summarize the latest findings on the mechanism of noncoding RNA-mediated programmed cell death on bone homeostasis imbalance leading to osteoporosis. And we provide a deeper understanding of the role played by the noncoding RNA-programmed cell death axis at the gene regulatory level of osteoporosis. We hope to provide a unique opportunity to develop novel diagnostic and therapeutic approaches for osteoporosis.

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“…Physiologically, pyroptosis is a key cellular inflammatory response against extracellular pathogens like microbial and viral infections, ligands, or cellular perturbations [32]. However, pyroptosis is also known to play a critical role in various inflammatory diseases [33, 34]. Pyroptosis belongs to the innate immune response and can be classified as a cell death form orchestrated through canonical and/or non-canonical signaling pathways involving members of the gasdermin (GSDM) family.…”

Section: Introductionmentioning

confidence: 99%

Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?

Frørup,

Svane,

Henriksen

et al. 2024

Preprint

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Immune-mediated destruction of the beta-cells in the pancreatic islets of Langerhans is the underlying cause of type 1 diabetes (T1D). Despite decades of research, the exact mechanisms involved at the beta-cell level during the development of disease remain poorly understood. This includes the mode(s) of beta-cell death and signaling events implicated in exacerbating local islet inflammation and immune cell infiltration, commonly known as insulitis. In disease models, beta-cell apoptosis seems to be the predominant cell death form which has led to the general assumption that beta cells mostly die by apoptosis in T1D. However, apoptosis is an anti-inflammatory programmed cell death mechanism, and this dogma is therefore challenged by the pathogenetic nature of T1D, as a progressive increase in islet inflammation is seen. This infers that other modes of beta-cell death that inherently increase insulitis may predominate. One such mechanism could be the newly characterized form of programmed cell death; pyroptosis (from the Greek 'fire-falling'). Pyroptosis is characterized by gasdermin-mediated cell lysis with a bursting release of pro-inflammatory factors. Beta-cell death by pyroptosis in T1D may therefore offer a plausible explanation for the exacerbated paracrine islet inflammation that spreads during the progression of insulitis. Here, we briefly debate the evidence supporting beta-cell pyroptosis in T1D as a central mechanism of islet inflammation and beta-cell demise. The paper intends to challenge the current understanding of beta-cell destruction to move the field forward. Importantly, we present experimental data from human islets and EndoC-βH5 cells that directly support beta-cell pyroptosis as a rational death mechanism in T1D. We suggest a model of beta-cell demise in T1D in which pyroptosis plays a prominent role in concert with other cell death mechanisms. As the role of pyroptosis in disease is still in its infancy, we hope also to inspire researchers working in other disease fields.

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Molecular Characteristics of Cell Pyroptosis and Its Inhibitors: A Review of Activation, Regulation, and Inhibitors

Cited by 13 publications

References 154 publications

Antagonistic nanobodies reveal mechanism of GSDMD pore formation and unexpected therapeutic potential

Antagonistic nanobodies reveal mechanism of GSDMD pore formation and unexpected therapeutic potential

Noncoding RNAs: the crucial role of programmed cell death in osteoporosis

Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?

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