RESUMEN
BACKGROUND: Intracranial aneurysm (IA) is the most common cerebrovascular disease, and subarachnoid hemorrhage caused by its rupture can seriously impede nerve function. Pyroptosis is an inflammatory mode of cell death whose underlying mechanisms involving the occurrence and rupture of IAs remain unclear. In this study, using bioinformatics analysis, we identified the potential pyroptosis-related genes (PRGs) and performed their inflammatory response mechanisms in IAs. METHODS: The mRNA expression matrix of the IA tissue was obtained from the Gene Expression Omnibus database, and 51 PRGs were obtained from previous articles collected from PubMed. The differentially expressed PRGs (DEPRGs) were performed using R software. Subsequently, we performed enrichment analysis, constructed a protein-protein interaction network, performed weighted gene coexpression network analysis (WGCNA) and external validation using another dataset, and identified a correlation between hub genes and immune cell infiltration. Finally, the expression and tissue distribution of these hub genes in IA tissues were detected using Western blotting and immunohistochemical (IHC) staining. RESULTS: In total, 12 DEPRGs associated with IA were identified in our analysis, which included 11 up-regulated and one down-regulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the DEPRGs were mostly enriched in the NOD-like receptor signaling pathway, interleukin-1 beta production, and the inflammasome complex. Three hub genes, NLRP3, IL1B and IL18, were identified using Cytoscape software and the WGCNA correlation module, and external validation revealed statistically significant differences between the expression of these hub genes in the ruptured and unruptured aneurysm groups (p < 0.05). Furthermore, all AUC values were > 0.75. Immune cell infiltration analysis suggested that the hub genes are related to CD8 T cell, macrophages and mast cells. Finally, IHC staining revealed that the protein levels of these hub genes were higher in ruptured and unruptured IA tissues than in normal tissues (p < 0.05). CONCLUSION: The results of bioinformatics analysis showed that pyroptosis is closely related to the formation and rupture of IA, and identified three potential hub genes involved in the pyroptosis and infiltration ofcells. Our findings may improve the understanding of the mechanisms underlying pyroptosis in IA.
Asunto(s)
Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/genética , Piroptosis/genética , Muerte Celular , Biología Computacional , Inflamación/genéticaRESUMEN
Usually, the massive elimination of cells under steady-state conditions occurs by apoptosis, which is also acknowledged to explain the loss of enterocytes in the small intestine of celiac disease (CD) patients. However, little is known about the role of proinflammatory cell death pathways in CD. Here, we have used confocal microscopy, western blot, and RT-qPCR analysis to assess the presence of regulated cell death pathways in the duodenum of CD patients. We found an increased number of dead (TUNEL+) cells in the lamina propria of small intestine of CD patients, most of them are plasma cells (CD138+). Many dying cells expressed FAS and were in close contact with CD3+ T cells. Caspase-8 and caspase-3 expression was increased in CD, confirming the activation of apoptosis. In parallel, caspase-1, IL-1ß, and GSDMD were increased in CD samples indicating the presence of inflammasome-dependent pyroptosis. Necroptosis was also present, as shown by the increase of RIPK3 and phosphorylate MLKL. Analysis of published databases confirmed that CD has an increased expression of regulated cell death -related genes. Together, these results reveal that CD is characterized by cell death of different kinds. In particular, the presence of proinflammatory cell death pathways may contribute to mucosal damage.
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Enfermedad Celíaca , Piroptosis , Humanos , Piroptosis/genética , Necroptosis/genética , Apoptosis/genética , Muerte CelularRESUMEN
PURPOSE: To assess the expression of genes that are relevant to pyroptosis and the relationship between these genes and prognosis in uterine corpus endometrial carcinoma (UCEC). METHODS: The research identifies 16 pyroptosis regulators with different expressions in normal endometrium and UCEC. In accordance with the differentially expressed genes (DEGs), the various kinds of UCEC are classified into two sub-types. With the help of the Cancer Genome Atlas (TCGA), the prognostic value of all pyroptosis-related genes for survival was assessed, and a multigene model has constructed accordingly. Ten genes were modeled by applying the minimum criteria for determining risk score selection (LASSO) Cox regression method. Meanwhile, by referring to the TCGA atlas, UCEC patients were divided into the high- and low-risk subgroups. The effects of the gene with significant differences on the proliferation of two cancer cells were also verified. RESULTS: The survival rate of UCEC cases with higher risk was higher than that with lower risk (P < 0.001). Through the median risk score of TCGA atlas, UCEC cases were ranked as patients with higher risk and patients with lower risk. The low risk has a significant relationship with the prolongation of overall survival (OS) (p = 0.001) in the low-risk subgroup. Moreover, the KEGG and gene ontology (GO) enrichment models indicated that among the patients in the high-risk subgroup, their immune-related genes were concentrated but with decreased immune status. CONCLUSION: The apoptosis-related genes are crucial for the immunity of tumors and may forecast the prognosis of UCEC.
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Carcinoma Endometrioide , Neoplasias Endometriales , Femenino , Humanos , Piroptosis/genética , Pronóstico , Apoptosis , Factores de Riesgo , Neoplasias Endometriales/genéticaRESUMEN
Klebsiella pneumoniae is a Gram-negative bacterium responsible for severe cases of nosocomial pneumonia. During the infectious process, both neutrophils and monocytes migrate to the site of infection, where they carry out their effector functions and can be affected by different patterns of cell death. Our data show that clinical strains of K. pneumoniae have dissimilar mechanisms for surviving within macrophages; these mechanisms include modulation of microbicidal mediators and cell death. The A28006 strain induced high IL-1ß production and pyroptotic cell death in macrophages; by contrast, the A54970 strain induced high IL-10 production and low IL-1ß production by macrophages. Pyroptotic cell death induced by the A28006 strain leads to a significant increase in bacterial sensitivity to hydrogen peroxide, and efferocytosis of the pyroptotic cells results in efficient bacterial clearance both in vitro and in vivo. In addition, the A54970 strain was able to inhibit inflammasome activation and pyroptotic cell death by inducing IL-10 production. Here, for the first time, we present a K. pneumoniae strain able to inhibit inflammasome activation, leading to bacterial survival and dissemination in the host. The understanding of possible escape mechanisms is essential in the search for alternative treatments against multidrug-resistant bacteria.
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Bacteriemia/microbiología , Interacciones Huésped-Patógeno/inmunología , Inflamasomas/inmunología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/patogenicidad , Piroptosis/inmunología , Animales , Bacteriemia/genética , Bacteriemia/inmunología , Bacteriemia/patología , Caspasa 1/deficiencia , Caspasa 1/genética , Caspasa 1/inmunología , Caspasas/deficiencia , Caspasas/genética , Caspasas/inmunología , Caspasas Iniciadoras , Femenino , Expresión Génica , Interacciones Huésped-Patógeno/genética , Humanos , Inflamasomas/genética , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-10/inmunología , Infecciones por Klebsiella/genética , Infecciones por Klebsiella/inmunología , Infecciones por Klebsiella/patología , Klebsiella pneumoniae/inmunología , Klebsiella pneumoniae/aislamiento & purificación , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/microbiología , Neutrófilos/inmunología , Neutrófilos/microbiología , Fagocitosis/genética , Piroptosis/genéticaRESUMEN
Inflammasomes are multiprotein platforms assembled in the cytosol in response to pathogens and cell stress. Inflammasomes are recognized by their important role on defenses against bacterial infections and have been also implicated in a range of human inflammatory disorders. Intracellular sensors such as NLRP1, NLRP3, NLRC4, AIM2 and Pyrin induce assembly of inflammasomes, while caspase-11 induces the non-canonical pathway for activation of the NLRP3 inflammasome. The formation of the inflammasome leads to caspase-1 activation that triggers pyroptosis and activation of interleukin-1ß (IL-1ß) and IL-18. Pyroptotic cell death and cytokines production are involved in restriction of bacterial replication by limiting the replication niche of intracellular bacteria and by inducing inflammatory responses. In this review we focus on the mechanisms mediated by inflammasome activation that leads to inflammatory responses and restriction of bacterial infection.
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Bacterias Gramnegativas/inmunología , Bacterias Grampositivas/inmunología , Interacciones Huésped-Patógeno , Inmunidad Innata , Inflamasomas/inmunología , Piroptosis/inmunología , Linfocitos T/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/inmunología , Caspasa 1/genética , Caspasa 1/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Regulación de la Expresión Génica , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/crecimiento & desarrollo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas NLR , Pirina/genética , Pirina/inmunología , Piroptosis/genética , Transducción de Señal , Linfocitos T/microbiologíaRESUMEN
Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires' disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F1 mice in a mixed 129 × C57BL/6 background deficient (129 × Casp-11(-/-) ) or sufficient (129 × C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo.