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Cell Jan 2024Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by... (Review)
Review
Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.
Topics: Humans; Apoptosis; Cell Death; Ferroptosis; Homeostasis; Pyroptosis; Signal Transduction
PubMed: 38242081
DOI: 10.1016/j.cell.2023.11.044 -
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 -
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 -
Experimental & Molecular Medicine Aug 2023Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but... (Review)
Review
Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases.
Topics: Humans; Cell Death; Apoptosis; Necrosis; Pyroptosis; Inflammation
PubMed: 37612413
DOI: 10.1038/s12276-023-01078-x -
Journal of Translational Medicine Jul 2023Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus (DM). A growing body of research has demonstrated that the inflammatory...
BACKGROUND
Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus (DM). A growing body of research has demonstrated that the inflammatory state plays a critical role in the incidence and development of DN. Pyroptosis is a new way of programmed cell death, which has the particularity of natural immune inflammation. The inhibition of inflammatory cytokine expression and regulation of pathways related to pyroptosis may be a novel strategy for DN treatment. The aim of this study is to identify pyroptosis-related genes and potential drugs for DN.
METHODS
DN differentially expressed pyroptosis-related genes were identified via bioinformatic analysis Gene Expression Omnibus (GEO) dataset GSE96804. Dataset GSE30528 and GSE142025 were downloaded to verify pyroptosis-related differentially expressed genes (DEGs). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a pyroptosis-related gene predictive model. A consensus clustering analysis was performed to identify pyroptosis-related DN subtypes. Subsequently, Gene Set Variation Analysis (GSVA), Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the differences between DN clusters. A protein-protein interaction (PPI) network was used to select hub genes and DGIdb database was utilized to screen potential therapeutic drugs/compounds targeting hub genes.
RESULTS
A total of 24 differentially expressed pyroptosis-related genes were identified in DN. A 16 gene predictive model was conducted via LASSO regression analysis. According to the expression level of these 16 genes, DN cases were divided into two subtypes, and the subtypes are mainly associated with inflammation, activation of immune response and cell metabolism. In addition, we identified 10 hub genes among these subtypes, and predicted 65 potential DN therapeutics that target key genes.
CONCLUSION
We identified two pyroptosis-related DN clusters and 65 potential therapeutical agents/compounds for DN, which might shed a light on the treatment of DN.
Topics: Humans; Diabetic Nephropathies; Pyroptosis; Apoptosis; Cluster Analysis; Computational Biology; Inflammation; Diabetes Mellitus
PubMed: 37480090
DOI: 10.1186/s12967-023-04350-w -
International Journal of Molecular... Oct 2023PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis,... (Review)
Review
PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis, necroptosis) concomitantly. Normally, cell death is recognized as a strategy to eliminate unnecessary cells, inhibit the proliferation of invaded pathogens and maintain homeostasis; however, vigorous cell death can cause excessive inflammation and tissue damage. Acute lung injury (ALI) and chronic obstructive pulmonary syndrome (COPD) exacerbation is related to several pathogens (e.g., influenza A virus, SARS-CoV-2) known to cause PANoptosis. An understanding of the mechanism and specific regulators may help to address the pathological systems of these diseases. This review presents our understanding of the potential mechanism of PANoptosis and the role of PANoptosis in different pulmonary diseases.
Topics: Humans; Apoptosis; Cell Death; Acute Lung Injury; Homeostasis; Inflammation; Pyroptosis
PubMed: 37895022
DOI: 10.3390/ijms242015343 -
Seminars in Immunology Nov 2023Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed... (Review)
Review
Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.
Topics: Humans; Neutrophils; Pyroptosis; Phagocytosis; Apoptosis
PubMed: 37939552
DOI: 10.1016/j.smim.2023.101849 -
Cell Death & Disease Sep 2023Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role...
Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role remains unclear in psoriasis as one chronic inflammatory skin disorder with high prevalence. We found that N-terminal GSDMD (N-GSDMD) was aberrantly expressed in epidermis of skin lesion in psoriasis patients and imiquimod-induced psoriasis-like dermatitis (IIPLD) mice. In epidermis of IIPLD mice and M5 (simulating psoriatic inflammatory challenge)-treated keratinocytes cultured in vitro, cleavage products of caspase-1, GSDMD and IL-1β were increased. M5-stimulated keratinocyte presented typical pyroptosis morphology accompanied with PI-staining. Gsdmd keratinocytes could not present pyroptosis morphology while stimulated with M5. Electroporation of recombinant N-GSDMD could make the pyroptosis morphology reappear. In Gsdmd mice or keratinocyte-specific Gsdmd conditional knockout mice, we observed the alleviation of psoriatic inflammation and epidermal aberrant expression of Ki-67 and differentiation markers (loricrin and keratin 5) after imiquimod stimulation. Transplanting skin tissue from control mice to Gsdmd mice can evoke the response to imiquimod stimulation in the background of Gsdmd mice (not limited in transplanting area). In M5-stimulated keratinocytes, disulfiram or GSDMD siRNA transfection can inhibit pyroptosis and eliminate disproportionate increases of Ki-67 and PI. We further validated that topically application of disulfiram (pyroptosis inhibitor) also alleviated IIPLD in mice. These findings indicate a novel mechanism that GSDMD-mediated keratinocyte pyroptosis facilitates hyperproliferation and aberrant differentiation induced by immune microenvironment in psoriatic skin inflammation, which contributes to pathogenesis of psoriasis. Our study provides an innovative insight that targeting pyroptosis can be considered as a therapeutic strategy against psoriasis.
Topics: Animals; Mice; Gasdermins; Disulfiram; Imiquimod; Ki-67 Antigen; Pyroptosis; Keratinocytes; Psoriasis; Dermatitis; Inflammation
PubMed: 37673869
DOI: 10.1038/s41419-023-06094-3 -
Journal of Neuroinflammation Nov 2023Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated...
BACKGROUND
Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated with tumours and inflammatory diseases. However, the role of TRIM45 in SAE and the relationship between TRIM45 and microglial pyroptosis are unknown. In this study, we found that TRIM45 played an important role in regulating microglial pyroptosis and the molecular mechanism.
METHODS
SAE was induced by intraperitoneal injection of LPS in WT and AAV-shTRIM45 mice. BV2 cells were treated with LPS/ATP in vitro. Cognitive function was assessed by the Morris water maze. Nissl staining was used to evaluate histological and structural lesions. ELISA was used to dectect neuroinflammation. qPCR was used to detect the mRNA levels of inflammatory cytokines, NLRP3, and autophagy genes. Western blotting and immunofluorescence analysis were used to analyse the expression of the proteins. Changes in reactive oxygen species (ROS) in cells were observed by flow cytometry. Changes in mitochondrial membrane potential in BV2 cells were detected by JC-1 staining. Peripheral blood mononuclear cells were extracted from blood by density gradient centrifugation and then used for qPCR, western blotting and flow detection. To further explore the mechanism, we used the overexpression plasmids TRIM45 and Atg5 as well as siRNA-TRIM45 and siRNA-Atg5 to analyse the downstream pathway of NLRP3. The protein and mRNA levels of TRIM45 in peripheral blood mononuclear cells from sepsis patients were examined.
RESULTS
Knocking down TRIM45 protected against neuronal damage and cognitive impairment in septic mice. TRIM45 knockdown inhibited microglial pyroptosis and the secretion of inflammatory cytokines in vivo and in vitro, which was mediated by NLRP3/Gsdmd-N activation. Overexpression of TRIM45 could activate NLRP3 and downstream proteins. Further examination showed that TRIM45 regulated the activation of NLRP3 by altering Atg5 and regulating autophagic flux. It was also found that overexpression and knockdown of TRIM45 affected the changes in ROS and mitochondrial membrane potential. Thus, knocking down TRIM45 could reduce microglial pyroptosis, the secretion of proinflammatory cytokines, and neuronal damage and improve cognitive function. In addition, the level of TRIM45 protein in septic patients was increased. There was a positive linear correlation between APACHE II score and TRIM45, between SOFA score and TRIM45. Compared to group GCS > 9, level of TRIM45 were increased in group GCS ≤ 8.
CONCLUSION
TRIM45 plays a key role in neuroinflammation caused by LPS, and the mechanism may involve TRIM45-mediated exacerbation of microglial pyroptosis via the Atg5/NLRP3 axis.
Topics: Animals; Humans; Mice; Cytokines; Inflammasomes; Leukocytes, Mononuclear; Lipopolysaccharides; Microglia; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Reactive Oxygen Species; Repressor Proteins; RNA, Messenger; RNA, Small Interfering; Sepsis-Associated Encephalopathy
PubMed: 38037161
DOI: 10.1186/s12974-023-02959-8 -
Nature Communications Jul 2023Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to...
Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.
Topics: Animals; Mice; Female; Pyroptosis; Gasdermins; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37454146
DOI: 10.1038/s41467-023-39938-9