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Experimental & Molecular Medicine Aug 2023Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically,... (Review)
Review
Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
Topics: Apoptosis; Mitochondria; Cell Death; Pyroptosis
PubMed: 37612409
DOI: 10.1038/s12276-023-01046-5 -
Nature Reviews. Drug Discovery May 2021Gasdermins were recently identified as the mediators of pyroptosis - inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals.... (Review)
Review
Gasdermins were recently identified as the mediators of pyroptosis - inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals. Upon activation, gasdermins form cell membrane pores, which release pro-inflammatory cytokines and alarmins and damage the integrity of the cell membrane. Roles for gasdermins in autoimmune and inflammatory diseases, infectious diseases, deafness and cancer are emerging, revealing potential novel therapeutic avenues. Here, we review current knowledge of the family of gasdermins, focusing on their mechanisms of action and roles in normal physiology and disease. Efforts to develop drugs to modulate gasdermin activity to reduce inflammation or activate more potent immune responses are highlighted.
Topics: Animals; Anti-Inflammatory Agents; Cytokines; Humans; Immunity; Inflammation Mediators; Neoplasm Proteins; Pyroptosis
PubMed: 33692549
DOI: 10.1038/s41573-021-00154-z -
Annual Review of Pathology Jan 2022The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic... (Review)
Review
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on () signals and mechanisms of inflammasome activation, () the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and () potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Pyroptosis
PubMed: 34752711
DOI: 10.1146/annurev-pathmechdis-032521-102529 -
Journal of Experimental & Clinical... Aug 2021Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention.... (Review)
Review
Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.
Topics: Animals; Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Immunity; Neoplasms; Pyroptosis; Signal Transduction; Treatment Outcome
PubMed: 34429144
DOI: 10.1186/s13046-021-02065-8 -
Frontiers in Immunology 2022Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and... (Review)
Review
Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1β, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.
Topics: Biological Phenomena; Inflammasomes; Intracellular Signaling Peptides and Proteins; Phosphate-Binding Proteins; Pyroptosis
PubMed: 35774778
DOI: 10.3389/fimmu.2022.893912 -
Cell Research Dec 2023Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear....
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME or GSDME knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
Topics: Humans; Animals; Mice; Pyroptosis; Mannose; AMP-Activated Protein Kinases; Gasdermins
PubMed: 37460805
DOI: 10.1038/s41422-023-00848-6 -
Molecular Aspects of Medicine Dec 2020Inflammasomes are large cytosolic multiprotein complexes assembled in response to infection and cellular stress, and are crucial for the activation of inflammatory... (Review)
Review
Inflammasomes are large cytosolic multiprotein complexes assembled in response to infection and cellular stress, and are crucial for the activation of inflammatory caspases and the subsequent processing and release of pro-inflammatory mediators. While caspase-1 is activated within the canonical inflammasome, the related caspase-4 (also known as caspase-11 in mice) and caspase-5 are activated within the non-canonical inflammasome upon sensing of cytosolic lipopolysaccharide (LPS) from Gram-negative bacteria. However, the consequences of canonical and non-canonical inflammasome activation are similar. Caspase-1 promotes the processing and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and the release of danger signals, as well as a lytic form of cell death called pyroptosis, whereas caspase-4, caspase-5 and caspase-11 directly promote pyroptosis through cleavage of the pore-forming protein gasdermin D (GSDMD), and trigger a secondary activation of the canonical NLRP3 inflammasome for cytokine release. Since the presence of the non-canonical inflammasome activator LPS leads to endotoxemia and sepsis, non-canonical inflammasome activation and regulation has important clinical ramifications. Here we discuss the mechanism of non-canonical inflammasome activation, mechanisms regulating its activity and its contribution to health and disease.
Topics: Animals; Caspases; Humans; Inflammasomes; Inflammation Mediators; Lipopolysaccharides; Mice; Pyroptosis
PubMed: 33187725
DOI: 10.1016/j.mam.2020.100924 -
Frontiers in Immunology 2022Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death.... (Review)
Review
Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.
Topics: Endothelial Cells; Hepatocytes; Humans; Inflammasomes; Liver Cirrhosis; Pyroptosis
PubMed: 35707547
DOI: 10.3389/fimmu.2022.896473 -
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 -
Science (New York, N.Y.) Jul 2022Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that...
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1 abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1 to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.
Topics: Anisomycin; CARD Signaling Adaptor Proteins; Humans; Inflammasomes; Keratinocytes; MAP Kinase Kinase Kinases; Mutation; NLR Proteins; Neoplasm Proteins; Phosphorylation; Pyroptosis; Ribosomes; Stress, Physiological; Ultraviolet Rays
PubMed: 35857590
DOI: 10.1126/science.abl6324