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Caspase-1-licensed lung epithelial cell pyroptosis drives infiltrating neutrophil necroptosis to dampen immune defense against pulmonary bacterial infection

ABSTRACT: Caspase-1-licensed lung epithelial cell pyroptosis drives infiltrating neutrophil necroptosis to dampen immune defense against pulmonary bacterial infection

PROVIDER: PRJNA1015213 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26034396_1.fastq.gz	Fastqsanger.gz
	SRR26034396_2.fastq.gz	Fastqsanger.gz
	SRR26034397_1.fastq.gz	Fastqsanger.gz
	SRR26034397_2.fastq.gz	Fastqsanger.gz
	SRR26034398_1.fastq.gz	Fastqsanger.gz

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Caspase-1-licensed lung epithelial cell pyroptosis drives infiltrating neutrophil necroptosis to dampen immune defense against pulmonary bacterial infection

Project description:Lower respiratorytractinfections, especially those caused by bacteria, are responsible for a large number of deaths each year and are a leading global health issue. Pulmonary bacterial infection causes a severe host response and cell death, such as pyroptosis and necroptosis. However, its pathogenesis is complicated, and whether these different types of cell death communicate with each other and whether these communications are involved in the process of infection remains unknown. Here, we showed that the global deficiency of caspase-1 can protect against lethal pulmonary E. coli infection by reducing the necroptosis of infiltrated neutrophils, which are key players in immune responses in the lung. Mechanistically, neutrophil necroptosis was not directly triggered in a cell-intrinsic manner by invading bacteria. Activation of caspase-1 led to remarkable pyroptotic death of lung epithelial cells, which facilitated the release of intracellular dsRNA. The dsRNA was subsequently taken up by neutrophils and bound to ZBP1 to trigger neutrophil necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrated a paradigm of communication between necroptosis and pyroptosis in different cell types cooperated by microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.

2025-06-05 | GSE242879 | GEO

Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Project description:Caspase-8 and FADD play key roles in the regulation of cell death by necroptosis. The absence of either protein results in early embryonic lethality due to the activation of the kinase RIPK3 and its phosphorylation of the necroptosis executioner, MLKL. We genetically engineered and characterized a mouse model to monitor MLKL phosphorylation in the absence of necroptosis in vivo. Ablation of caspase-8 or FADD resulted in the transcriptional upregulation in several tissues of ZBP1, a cytosolic nucleic acid sensor capable of activating RIPK3, and ZBP1 was required for spontaneous phosphorylation of MLKL. Our findings provide a novel mechanism by which the FADD-Caspase-8 complex prevents necroptosis.

2022-09-19 | GSE208744 | GEO

ZBP1 is a cytosolic RNA virus sensor driving activation of the NLRP3 inflammasome, pyroptosis, necroptosis and apoptosis

Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.

2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress

ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

Project description:Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl, and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many mucosal epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl. Intriguingly, expression of ZBP1 was elevated in Casp8-/- Tnfr1-/- embryos prior to their succumbing to aberrant necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because rare Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. Of note, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5-7 weeks of being born, which is not seen in Casp8-/- Ripk1-/- Trif-/- Zbp1-/-, Casp8-/- Ripk3-/-, or Casp8-/- Mlkl-/- mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.

2024-04-01 | GSE254754 | GEO

Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Project description:Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

| PRJNA860938 | ENA

Citric acid, an ovarian cancer metabolite, induces pyroptosis via caspase-4/TXNIP-NLRP3-GSDMD pathway in ovarian cancer

Project description:Malignant tumors display profound changes in cellular metabolism, yet how these altered metabolites affect the development and growth of tumors is not fully understood. Here, we used metabolomics to analyze the metabolic profile differences in ovarian cancer, and found that citric acid (CA) is the most significantly downregulated metabolite. Recently, CA has been reported to inhibit the growth of a variety of tumor cells, but whether it is involved in pyroptosis of ovarian cancer and its potential molecular mechanisms still remains to be further investigated. Here, we demonstrated that CA inhibits the growth of ovarian cancer cells in a dose-dependent manner. RNA-seq analysis revealed that CA significantly promoted the expression of thioredoxin interacting protein (TXNIP) and caspase-4 (CASP4). Morphologic examination by transmission electron microscopy indicated that CA-treated ovarian cancer cells exhibited typical pyroptosis characteristics. Further mechanistic analyses showed that CA facilitates pyroptosis via CASP4/TXNIP-NLRP3-Gesdermin-d (GSDMD) pathway in ovarian cancer. This study elucidated that CA induces ovarian cancer cell death through classical and non-classical pyroptosis pathways, which may be beneficial as an ovarian cancer therapy.

2022-08-01 | GSE189851 | GEO

Nigericin induced paraptosis-like cell death instead of pyroptosis in corneal keratocytes

Project description:Corneal wound healing involves complex cellular processes, including keratocyte cell death, which plays a pivotal role in initiating tissue repair. Recent studies suggest that pyroptosis, characterized by the release of pro-inflammatory factors, occurs during tissue repair which may also contribute to the inflammatory phase of corneal wound healing. In this study, we investigated the nature of cell death in human keratocytes treated with nigericin, a known pyroptosis inducer. Surprisingly, nigericin triggered a unique form of non-inflammatory cell death marked by extensive vacuolation, resembling paraptosis. Proteomic analysis revealed that our human keratocytes lack key components of the canonical pyroptosis pathway, including NLRP3, ASC, and caspase-1, potentially explaining the absence of pyroptosis in these cells. This process was further confirmed by the absence of caspase-3 activation and lack of ER stress, alongside increased autophagic marker LC3-II accumulation. These findings suggest that nigericin triggers a paraptosis-like cell death in keratocytes, rather than pyroptosis, highlighting an alternative mechanism of cell death in corneal wound healing that warrants further exploration.

2025-06-30 | PXD058468 | Pride

Post-transcriptional regulation of necroptosis gene EIF2AK2 in peripheral blood of bronchopulmonary dysplasia

Project description:Bronchopulmonary dysplasia (BPD) remains the most frequent chronic lung disease among infants, which involves multifactorial pathogenesis. Necroptosis represents a caspase-independent mode of programmed cell death, and its deregulation associates with lung diseases, but the mechanisms of necroptosis during BPD are indistinct. This work was conducted for unveiling the post-transcriptional regulatory mechanisms of necroptosis in BPD.

2024-02-21 | GSE219156 | GEO

Unexpected cross-talk between the pathogen defense mechanisms of apoptosis, necroptosis, and pyroptosis.

Project description:Unexpected cross-talk between the pathogen defense mechanisms of apoptosis, necroptosis, and pyroptosis.

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ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

Project description:ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

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