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Endogenous tRNA-derived small RNA (tRF3-Thr-AGT) inhibits ZBP1/NLRP3 pathway-mediated cell pyroptosis to attenuate acute pancreatitis (AP).

ABSTRACT: Endogenous transfer RNA-derived small RNAs (tsRNAs) are newly identified RNAs that are closely associated with the pathogenesis of multiple diseases, but the involvement of tsRNAs in regulating acute pancreatitis (AP) development has not been reported. In this study, we screened out a novel tsRNA, tRF3-Thr-AGT, that was aberrantly downregulated in the acinar cell line AR42J treated with sodium taurocholate (STC) and the pancreatic tissues of STC-induced AP rat models. In addition, STC treatment suppressed cell viability, induced pyroptotic cell death and cellular inflammation in AP models in vitro and in vivo. Overexpression of tRF3-Thr-AGT partially reversed STC-induced detrimental effects on the AR42J cells. Next, Z-DNA-binding protein 1 (ZBP1) was identified as the downstream target of tRF3-Thr-AGT. Interestingly, upregulation of tRF3-Thr-AGT suppressed NOD-like receptor protein 3 (NLRP3)-mediated pyroptotic cell death in STC-treated AR42J cells via degrading ZBP1. Moreover, the effects of tRF3-Thr-AGT overexpression on cell viability and inflammation in AR42J cells were abrogated by upregulating ZBP1 and NLRP3. Collectively, our data indicated that tRF3-Thr-AGT suppressed ZBP1 expressions to restrain NLRP3-mediated pyroptotic cell death and inflammation in AP models. This study, for the first time, identified the role and potential underlying mechanisms by which tRF3-Thr-AGT regulated AP pathogenesis.

SUBMITTER: Sun B

PROVIDER: S-EPMC8581331 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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

Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis.

Project description:ObjectivesWedelolactone exhibits regulatory effects on some inflammatory diseases. However, the anti-inflammatory mechanism of wedelolactone has not been entirely unravelled. Therefore, the present study focuses on investigating the mechanism of wedelolactone on NLRP3 inflammasome in macrophages and its influence on MSU-induced inflammation.Materials and methodsBMDM, J774A.1 and PMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with ATP or nigericin or MSU crystal in the presence or absence of wedelolactone. The cell lysates and supernatants were collected to detect NLRP3 inflammasome components such as NLRP3, ASC and caspase 1, as well as pyroptosis and IL-1β production. In addition, the anti-inflammatory effects of wedelolactone on MSU-induced peritonitis and arthritis mice were also evaluated.ResultsWe found that wedelolactone broadly inhibited NLRP3 inflammasome activation and pyroptosis and IL-1β secretion. Wedelolactone also block ASC oligomerization and speck formation. The inhibitory effects of wedelolactone were abrogated by PKA inhibitor H89, which also attenuated wedelolactone-enhanced Ser/Thr phosphorylation of NLRP3 at PKA-specific sites. Importantly, wedelolactone could abate MSU-induced IL-1β production and neutrophils migration into peritoneal cavity, and reduced caspase 1 (p20) and IL-1β expression in the joint tissue of MSU-induced arthritis.ConclusionOur results indicate that wedelolactone promotes the Ser/Thr phosphorylation of NLRP3 to inhibit inflammasome activation and pyroptosis partly through potentiating PKA signalling, thus identifying its potential use for treating MSU-induced peritonitis and gouty arthritis.

| S-EPMC7507381 | biostudies-literature

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

2016-08-11 | GSE77611 | GEO

ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis).

Project description:Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.

| S-EPMC7939383 | biostudies-literature

Progress of pyroptosis in acute pancreatitis.

Project description: Not available

| S-EPMC8478374 | biostudies-literature

<i>Polygonatum sibiricum</i> Polysaccharides Attenuate Lipopoly-Saccharide-Induced Septic Liver Injury by Suppression of Pyroptosis via NLRP3/GSDMD Signals.

Project description:Sepsis is a systemic inflammatory response syndrome with high mortality. Acute liver injury is an independent predictor for poor prognosis in septic patients. Polygonatum sibiricum polysaccharides (PSP) have been reported to possess anti-inflammatory and hepatoprotective activities. To evaluate the effects of PSP on septic liver injury and demonstrate the potential molecular mechanisms, the septic acute liver injury (SALI) model was established in BALB/c mice via intraperitoneal injection of lipopolysaccharide (LPS). We found that PSP treatment could remarkably reduce the 48 h mortality rate of septic mice; alleviate liver histopathologic damage; lower the activity of neutrophil infiltration marker MPO in liver tissue; and decrease the levels of liver function indexes AST, ALT, ALP, and TBIL, inflammatory cytokines TNFα and IL-6, and pyroptosis-related inflammatory cytokines IL-18 and IL-1β in serum. TUNEL staining and detecting GSDMD-NT protein expression level in liver tissue revealed that PSP could restrain excessive pyroptosis. In addition, PSP treatment reversed the upregulations of mRNA expression levels of the NLRP3/GSDMD signals in the liver. Our results indicated the potential protective role of PSP against SALI by inhibiting pyroptosis via NLRP3/GSDMD signals.

| S-EPMC9500967 | biostudies-literature

Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis.

Project description:Nucleic acids are potent triggers for innate immunity. Double-stranded DNA and RNA adopt different helical conformations, including the unusual Z-conformation. Z-DNA/RNA is recognised by Z-binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM-1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock-in models, we report that mutation of key amino acids involved in Z-DNA/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Intact ZBP1-ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross-linked to endogenous RNA These observations show that Z-RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP1.

| S-EPMC5579359 | biostudies-literature

Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis.

Project description:BackgroundOsteoarthritis (OA) is the common chronic degenerative joint bone disease that is mainly featured by joint stiffness and cartilage degradation. Icariin (ICA), an extract from Epimedium, has been preliminarily proven to show anti-osteoporotic and anti-inflammatory effects in OA. However, the underlying mechanisms of ICA on chondrocytes need to be elucidated.MethodsLPS-treated chondrocytes and monosodium iodoacetate (MIA)-treated Wistar rats were used as models of OA in vitro and in vivo, respectively. LDH and MTT assays were performed to detect cytotoxicity and cell viability. The expression levels of NLRP3, IL-1?, IL-18, MMP-1, MMP-13, and collagen II were detected by qRT-PCR and Western blotting. The release levels of IL-1? and IL-18 were detected by ELISA assay. Caspase-1 activity was assessed by flow cytometry. Immunofluorescence and immunohistochemistry were used to examine the level of NLRP3 in chondrocytes and rat cartilage, respectively. The progression of OA was monitored with hematoxylin-eosin (H&E) staining and safranin O/fast green staining.ResultsICA could suppress LPS-induced inflammation and reduction of collagen formation in chondrocytes. Furthermore, ICA could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway to alleviate pyroptosis induced by LPS. Overexpression of NLRP3 reversed the above changes caused by ICA. It was further confirmed in the rat OA model that ICA alleviated OA by inhibiting NLRP3-mediated pyroptosis.ConclusionICA inhibited OA via repressing NLRP3/caspase-1 signaling-mediated pyroptosis in models of OA in vitro and in vivo, suggesting that ICA might be a promising compound in the treatment of OA.

| S-EPMC6737611 | biostudies-literature

NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages.

Project description:A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20?Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1? as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5?Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation.

| S-EPMC5386456 | biostudies-other

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation.

Project description:Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid-binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis.

| S-EPMC7336309 | biostudies-literature

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