Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1054555 | ENA |
REPOSITORIES: ENA
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Project description:NINJ1 mediates inflammatory cell death, PANoptosis, and drives lethality during heat stress
| PRJNA1061511 | ENA
Project description:Innate immunity provides the first line of defense through key mechanisms, including pyrogen and cytokine production and cell death. While elevated body temperature during infection is beneficial, heat stress (HS) can lead to inflammation and pathology. Links between HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during HS remain unclear. Here, we use diverse genetic approaches to elucidate innate immune pathways in HS. Our results show that bacteria and LPS robustly increase inflammatory cell death, PANoptosis, during HS. NINJ1 is the key executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioners. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients experiencing HS.
2024-01-05 | GSE252609 | GEO
Project description:Alcohol-associated liver disease (ALD) is a chronic inflammatory condition in which the innate immune pathways driving liver injury are not fully defined. In this study, we used clinical liver and serum samples, together with mouse models of ALD, to investigate the role of the innate immune sensors in disease pathogenesis. We observed increased ZBP1 expression in patients with ALD, with levels correlated with disease progression. Ethanol exposure induced ZBP1-dependent inflammatory cell death (PANoptosis) in both immune cells (including macrophages, monocytes, and Kupffer cells) and non-immune cells (hepatocytes). Basal ZBP1 expression was upregulated by the interferon regulatory factors IRF1 and IRF9, and ZBP1 activation engaged a PANoptotic pathway, where caspase-8 was a central regulator; the cell death was executed by NINJ1-mediated membrane rupture, independent of gasdermin D, gasdermin E, and MLKL. In ALD mouse models, Zbp1-deficient animals were significantly protected from liver injury and pathology. ZBP1 and NINJ1 expression were also elevated in liver and serum from patients with ALD, supporting their potential as disease biomarkers. Together, these data define an IRF–ZBP1–caspase-8–NINJ1 axis as a key driver of inflammatory cell death in ALD and a potential target for therapeutic intervention.
2025-12-08 | GSE311244 | GEO
Project description:Ferroptosis is a regulated form of necrotic cell death caused by an iron-dependent accumulation of oxidized phospholipids in cellular membranes, which culminates in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death executors. Yet, whether ferroptosis-associated PMR is actively executed by a protein or driven by osmotic pressure remains unknown. Here, we investigated the role of ninjurin-1 (NINJ1), the recently identified executor of pyroptosis-associated PMR, in ferroptosis. We report that during ferroptosis NINJ1 oligomerizes and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the early steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx and cell swelling. By contrast, NINJ1 is required for early loss of plasma membrane integrity, an event that precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular patterns (DAMPs) from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
2024-02-15 | PXD047622 | Pride
Project description:The deficiency of LKB1 in tumor cells impairs their ability to sense metabolic stress appropriately,ultimately leading to redox imbalance. LKB1-deficient NSCLC cells predominantly take up ascorbic acid. Inflammatory PCD, including necroptosis, pyroptosis and PANoptosis, could release inflammatory mediators and switch the inflammatory state of TIME. Previous study demonstrated that high-dose AA could promote lung cancer cell death, but the modality of cell death still remained unclear. To further investigated the precise modality of the above inflammatory PCD, we performed RNA sequencing on cells with deficient or intact LKB1 pretreated with high-dose AA or not and then analyzed the established different forms of programmed cell death signaling gene.
2025-06-28 | GSE269742 | GEO
Project description:Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wildtype mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1–dependent manner. Our findings suggest that ADAR1 suppresses ZBP1–mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to inform therapeutic strategies for cancer and other diseases.
2021-10-19 | GSE184323 | GEO
Project description:We have identified mouse Ninj1 as a protein responsible for plasma membrane integrity following cell death stimuli. Ninj1 KO BMDMs have a distinct bubble morphology wherein cell cytoplasmic contents fail to be released following cell death. To determine contributing factors to Ninj1 KO morphology, we performed RNAseq in WT and Ninj1 KO murine BMDMs with or without priming.
2020-12-18 | GSE156395 | GEO
Project description:PANoptosis is a novel type of cell death triggered by the cross-talk of three types of cell death (necrosis, apoptosis, and pyroptosis). Nevertheless, the molecular mechanisms associated with PANoptosis in thyroid cancer (TC) remain uncharted. Therefore, this study explored the effect of TFRC on PANoptosis in TC cells in vitro.
2025-08-31 | GSE280138 | GEO
Project description:Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 release. However, certain stimuli and cell types release IL-1 cytokines through GSDMD pores in cells that remain viable, a process termed hyperactivation. How these distinct cell fate choices are regulated downstream of GSDMD pore formation is unknown. Here, we demonstrate that the Card19 locus promotes lysis downstream of caspase activation. Despite being largely protected from cell death, CARD19-deficient macrophages had no defect in caspase activation, IL-1 secretion, or GSDMD cleavage. CARD19, a mitochondrial protein, was not responsible for the observed phenotypes, nor was the recently identified pore forming protein NINJ1 which regulates terminal pore formation during multiple forms of cell death. Furthermore, previously identified cell death phenotypes attributed to Sterile alpha and heat Armadillo motif-containing protein (SARM) were revealed to be caused by a passenger mutation. Importantly, Card19-/ mice had increased susceptibility to Yersinia infection, including increased mortality, higher bacterial burdens and pronounced splenomegaly. These findings implicate the Card19 locus as a factor that couples caspase processing and GSDMD cleavage to cell death, providing insight into how the checkpoint between hyperactivation and cell death is regulated.
2021-03-21 | GSE168489 | GEO
Project description:Ninjurin-1 (NINJ1), a protein recently linked to plasma membrane rupture (PMR) during inflammasome activation, plays a well-established role in cell death. However, its function in hematopoiesis has remained unexplored. In this study, we identify a novel, PMR-independent role for Ninj1 in regulating hematopoiesis using zebrafish models. Ninj1 deficiency resulted in significantly reduced neutrophil, erythrocyte, and hematopoietic stem/progenitor cell (HSPC) numbers, independently of its plasma membrane rupture (PMR) activity. Surprisingly, Ninj1 deficiency also alleviated neutrophilia and keratinocyte hyperproliferation in a chronic inflammation model, revealing a role beyond inflammasome-mediated cell death. To further investigate thisnoncanonical function, we identified PMR-deficient Ninj1 mutants (A56P and D50A). Expression of the A56P mutant rescued hematopoietic defects in Ninj1-deficient larvae, while the dominant-negative D50A mutant recapitulated the phenotypes of Ninj1 deficiency, confirming that Ninj1 regulates hematopoiesis independently of PMR. Furthermore, Ninj1 deficiency increased susceptibility to intracellular bacterial infection due to impaired neutrophil and macrophage recruitment, while overexpression of the A56P mutant enhanced immune cell recruitment and resistance to infection. Finally, we discovered that Ninj1 and Ninj2 cooperatively regulate the amplification of nascent hematopoietic stem cells (HSCs) from the hemogenic endothelium via canonical Wnt signaling. Importantly, this regulatory mechanism is conserved in human HSPCs, underscoring its evolutionary significance and translational potential. These findings position Ninjurins as critical regulators of HSC development and immune responses, with promising implications for enhancing HSC production in regenerative medicine and developing therapies for hematological and infectious diseases.
2026-07-02 | GSE330969 | GEO