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Acta Pharmacologica Sinica Oct 2022Pyroptosis, an inflammatory form of lytic cell death, is a type of cell death mediated by the gasdermin (GSDM) protein family. Upon recognizing exogenous or endogenous... (Review)
Review
Pyroptosis, an inflammatory form of lytic cell death, is a type of cell death mediated by the gasdermin (GSDM) protein family. Upon recognizing exogenous or endogenous signals, cells undergo inflammasome assembly, GSDM cleavage, the release of proinflammatory cytokines and other cellular contents, eventually leading to inflammatory cell death. In this review, we discuss the roles of the GSDM family for anti-cancer functions and various antitumor drugs that could activate the pyroptosis pathways.
Topics: Antineoplastic Agents; Cytokines; Inflammasomes; Neoplasm Proteins; Neoplasms; Pyroptosis
PubMed: 35288674
DOI: 10.1038/s41401-022-00887-6 -
Nature Reviews. Nephrology May 2023Pyroptosis is a form of regulated cell death that is mediated by the membrane-targeting, pore-forming gasdermin family of proteins. Pyroptosis was initially described as... (Review)
Review
Pyroptosis is a form of regulated cell death that is mediated by the membrane-targeting, pore-forming gasdermin family of proteins. Pyroptosis was initially described as a caspase 1- and inflammasome-dependent cell death pathway typified by the loss of membrane integrity and the secretion of cytokines such as IL-1β. However, gasdermins are now recognized as the principal effectors of this form of regulated cell death; activated gasdermins insert into cell membranes, where they form pores that result in the secretion of cytokines, alarmins and damage-associated molecular patterns and cause cell membrane rupture. It is now evident that gasdermins can be activated by inflammasome- and caspase-independent mechanisms in multiple cell types and that crosstalk occurs between pyroptosis and other cell death pathways. Although they are important for host antimicrobial defence, a growing body of evidence supports the notion that pyroptosis and gasdermins have pathological roles in cancer and several non-microbial diseases involving the gut, liver and skin. The well-documented roles of inflammasome activity and apoptosis pathways in kidney diseases suggests that gasdermins and pyroptosis may also be involved to some extent. However, despite some evidence for involvement of pyroptosis in the context of acute kidney injury and chronic kidney disease, our understanding of gasdermin biology and pyroptosis in the kidney remains limited.
Topics: Humans; Pyroptosis; Gasdermins; Inflammasomes; Cytokines; Kidney
PubMed: 36596918
DOI: 10.1038/s41581-022-00662-0 -
Seminars in Immunology Sep 2023Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous... (Review)
Review
Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response. Among the immune responses against intracellular bacteria, pyroptosis, a lytic form of cell death, is a crucial mechanism that eliminates replicative niches for intracellular pathogens and modulates the immune system by releasing danger signals. This review focuses on the role of pyroptosis in combating intracellular bacterial infection. We examine the cell type specific roles of pyroptosis in neutrophils and intestinal epithelial cells. We discuss the regulatory mechanisms of pyroptosis, including its modulation by autophagy and interferon-inducible GTPases. Furthermore, we highlight that while host-adapted pathogens can often subvert pyroptosis, environmental microbes are effectively eliminated by pyroptosis.
Topics: Humans; Pyroptosis; Cell Death; Neutrophils; Bacterial Infections; Bacteria
PubMed: 37429234
DOI: 10.1016/j.smim.2023.101805 -
Frontiers in Immunology 2021Sepsis 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... (Review)
Review
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.
Topics: Alarmins; Apoptosis; Caspases; Cytokines; Disseminated Intravascular Coagulation; Drugs, Chinese Herbal; Heart; Humans; Lung; Pyroptosis; Sepsis
PubMed: 34305952
DOI: 10.3389/fimmu.2021.711939 -
Apoptosis : An International Journal on... Apr 2023Pyroptosis could be responsible for the bone loss from bone metabolic diseases, leading to the negative impact on people's health and life. It has been shown that... (Review)
Review
Pyroptosis could be responsible for the bone loss from bone metabolic diseases, leading to the negative impact on people's health and life. It has been shown that osteoclasts, osteoblasts, macrophages, chondrocytes, periodontal and gingival cells may be involved in bone loss linked with pyroptosis. So far, the involved mechanisms have not been fully elucidated. In this review, we introduced the related cells involved in the pyroptosis associated with bone loss and summarized the role of these cells in the bone metabolism during the process of pyroptosis. We also discuss the clinical potential of targeting mechanisms in the osteoclasts, osteoblasts, macrophages, chondrocytes, periodontal and gingival cells touched upon pyroptosis to treat bone loss from bone metabolic diseases as well as the challenges of avoiding potential side effects and producing efficient treatment methods.
Topics: Humans; Pyroptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Apoptosis; Metabolic Diseases
PubMed: 36645574
DOI: 10.1007/s10495-022-01807-z -
Cell Death & Disease Feb 2023Pyroptosis is a recently described mechanism of programmed cell death mediated by proteins of the gasdermin family. Widely recognized signaling cascades include the... (Review)
Review
Pyroptosis is a recently described mechanism of programmed cell death mediated by proteins of the gasdermin family. Widely recognized signaling cascades include the classical, non-classical, caspase-3-dependent gasdermin E and caspase-8-dependent gasdermin D pathways. Additional pyroptotic pathways have been subsequently reported. With the rising prevalence of advanced age, the role of pyroptosis in the degenerative diseases of the elderly has attracted increased research attention. This article reviews the primary mechanisms of pyroptosis and summarizes progress in the research of degenerative diseases of the elderly such as presbycusis, age-related macular degeneration, Alzheimer's disease, intervertebral disc degeneration, and osteoarthritis.
Topics: Humans; Aged; Pyroptosis; Caspases; Gasdermins; Inflammasomes; Intracellular Signaling Peptides and Proteins; Neoplasm Proteins; Phosphate-Binding Proteins
PubMed: 36755014
DOI: 10.1038/s41419-023-05634-1 -
Cell Death & Disease Apr 2020Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane...
Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.
Topics: Antineoplastic Agents; Caspase 3; HeLa Cells; Humans; Palmitates; Pyroptosis; Transfection
PubMed: 32332857
DOI: 10.1038/s41419-020-2476-2 -
Journal of Neuroinflammation Jul 2022Pyroptosis is a programmed cell death characterized by swift plasma membrane disruption and subsequent release of cellular contents and pro-inflammatory mediators... (Review)
Review
Pyroptosis is a programmed cell death characterized by swift plasma membrane disruption and subsequent release of cellular contents and pro-inflammatory mediators (cytokines), including IL-1β and IL-18. It differs from other types of programmed cell death such as apoptosis, autophagy, necroptosis, ferroptosis, and NETosis in terms of its morphology and mechanism. As a recently discovered form of cell death, pyroptosis has been demonstrated to be involved in the progression of multiple diseases. Recent studies have also suggested that pyroptosis is linked to various ocular diseases. In this review, we systematically summarized and discussed recent scientific discoveries of the involvement of pyroptosis in common ocular diseases, including diabetic retinopathy, age-related macular degeneration, AIDS-related human cytomegalovirus retinitis, glaucoma, dry eye disease, keratitis, uveitis, and cataract. We also organized new and emerging evidence suggesting that pyroptosis signaling pathways may be potential therapeutic targets in ocular diseases, hoping to provide a summary of overall intervention strategies and relevant multi-dimensional evaluations for various ocular diseases, as well as offer valuable ideas for further research and development from the perspective of pyroptosis.
Topics: Apoptosis; Humans; Inflammasomes; Inflammation Mediators; Necroptosis; Pyroptosis
PubMed: 35836195
DOI: 10.1186/s12974-022-02547-2 -
Cancer Research Apr 2023Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress...
UNLABELLED
Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy.
SIGNIFICANCE
USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.
Topics: Animals; Mice; Apoptosis; Caspases; Gasdermins; Neoplasms; Pyroptosis; Tumor Microenvironment; Ubiquitin-Specific Proteases
PubMed: 36607699
DOI: 10.1158/0008-5472.CAN-22-1812 -
Seminars in Immunology Sep 2023Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming... (Review)
Review
Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming pores in the plasma membrane), and selective release of proinflammatory mediators. Induction of pyroptosis results in amplification of inflammation, contributing to the pathogenesis of chronic cardiovascular diseases such as atherosclerosis and diabetic cardiomyopathy, and acute cardiovascular events, such as thrombosis and myocardial infarction. While engagement of pyroptosis during sepsis-induced cardiomyopathy and septic shock is expected and well documented, we are just beginning to understand pyroptosis involvement in the pathogenesis of cardiovascular diseases with less defined inflammatory components, such as atrial fibrillation. Due to the danger that pyroptosis represents to cells within the cardiovascular system and the whole organism, multiple levels of pyroptosis regulation have evolved. Those include regulation of inflammasome priming, post-translational modifications of gasdermins, and cellular mechanisms for pore removal. While pyroptosis in macrophages is well characterized as a dramatic pro-inflammatory process, pyroptosis in other cell types within the cardiovascular system displays variable pathways and consequences. Furthermore, different cells and organs engage in local and distant crosstalk and exchange of pyroptosis triggers (oxidized mitochondrial DNA), mediators (IL-1β, S100A8/A9) and antagonists (IL-9). Development of genetic tools, such as Gasdermin D knockout animals, and small molecule inhibitors of pyroptosis will not only help us fully understand the role of pyroptosis in cardiovascular diseases but may result in novel therapeutic approaches inhibiting inflammation and progression of chronic cardiovascular diseases to reduce morbidity and mortality from acute cardiovascular events.
Topics: Animals; Humans; Pyroptosis; Gasdermins; Cardiovascular Diseases; Intracellular Signaling Peptides and Proteins; Neoplasm Proteins; Inflammasomes; Inflammation
PubMed: 37478801
DOI: 10.1016/j.smim.2023.101809