Inhibition of the PERK/TXNIP/NLRP3 Axis by Baicalin Reduces NLRP3 Inflammasome-Mediated Pyroptosis in Macrophages Infected with Mycobacterium tuberculosis
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ABSTRACT:
SUBMITTER: Fu Y
PROVIDER: S-EPMC8592748 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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Project description:Schistosomiasis is a parasitic helminth disease that can cause severe inflammatory pathology, leading to organ damage, in humans. During a schistosomal infection, the eggs are trapped in the host liver, and products derived from eggs induce a polarized Th2 cell response, resulting in granuloma formation and eventually fibrosis. Previous studies indicated that the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in schistosomiasis-associated liver fibrosis and that taurine could ameliorate hepatic granulomas and fibrosis caused by Schistosoma japonicum infection. Nevertheless, the precise role and molecular mechanism of the NLRP3 inflammasome and the protective effects of taurine in S. japonicum infection have not been extensively studied. In this study, we investigated the role of the NLRP3 inflammasome and the hepatoprotective mechanism of taurine in schistosoma-induced liver injury in mice. NLRP3 deficiency ameliorated S. japonicum-infection-induced hepatosplenomegaly, liver dysfunction, and hepatic granulomas and fibrosis; it also reduced NLRP3-dependent liver pyroptosis. Furthermore, taurine suppressed hepatic thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in mice with S. japonicum infections, thereby inhibiting the activation of downstream inflammatory mediators such as interleukin-1β and subsequent pyroptosis. Our results suggest that the TXNIP/NLRP3 inflammasome pathway and mediating pyroptosis are involved in S. japonicum-induced liver injury and may be a potential therapeutic target for schistosomiasis treatment. In addition, taurine may be useful to alleviate or to prevent the occurrence of schistosomiasis-associated liver fibrosis.
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Project description:The roles of thioredoxin-interacting protein (TXNIP) and receptor for advanced glycation end-products (RAGE)-dependent mechanisms of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-driven macrophage activation during acute lung injury are underinvestigated. Cultured THP-1 macrophages were treated with a RAGE agonist (S100A12), with or without a RAGE antagonist; cytokine release and intracytoplasmic production of reactive oxygen species (ROS) were assessed in response to small interfering RNA knockdowns of TXNIP and NLRP3. Lung expressions of TXNIP and NLRP3 and alveolar levels of IL-1β and S100A12 were measured in mice after acid-induced lung injury, with or without administration of RAGE inhibitors. Alveolar macrophages from patients with acute respiratory distress syndrome and from mechanically ventilated controls were analyzed using fluorescence-activated cell sorting. In vitro, RAGE promoted cytokine release and ROS production in macrophages and upregulated NLRP3 and TXNIP mRNA expression in response to S100A12. TXNIP inhibition downregulated NLRP3 gene expression and RAGE-mediated release of IL-1β by macrophages in vitro. In vivo, RAGE, NLRP3 and TXNIP lung expressions were upregulated during experimental acute lung injury, a phenomenon being reversed by RAGE inhibition. The numbers of cells expressing RAGE, NLRP3 and TXNIP among a specific subpopulation of CD16+CD14+CD206- ("pro-inflammatory") alveolar macrophages were higher in patients with lung injury. This study provides a novel proof-of-concept of complex RAGE-TXNIP-NLRP3 interactions during macrophage activation in acute lung injury.
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Project description:NLRP3 inflammasome-dependent pyroptosis has been implicated in liver fibrosis progression. However, the definite intrahepatic cell types that undergo pyroptosis and the underlying mechanism as well as the clinical importance remain unclear. Here, augmented levels of pyroptosis-related indicators GSDMD, IL-1β, and IL-18 were verified in both liver fibrosis patients and CCl4-induced fibrotic mouse model. Confocal imaging of NLRP3 with albumin, F4/80 or α-SMA revealed that enhanced NLRP3 was mainly localized to kupffer cells (KCs), indicating that KCs are major cell types that undergo pyroptosis. Targeting pyroptosis by inhibitor MCC950 attenuated the severity and ameliorated liver function in fibrosis models. In addition, elevated S100A8 in liver fibrosis patients was correlated with pyroptosis-related indicators. S100A8 stimulated pyroptotic death of macrophages, which resulted in activation of human hepatic stellate cell line LX-2 cells and increased collagen deposition. Mechanistically, S100A8 activated TLR4/NF-κB signaling and upregulated its target genes NLRP3, pro-IL-1β, and pro-IL-18 expression, and induced reactive oxygen (ROS) abundance to activate NLRP3 inflammasome, finally leading to pyroptotic cell death in macrophages. More importantly, circulating GSDMD had the optimal predicting value for liver fibrosis progression. In conclusion, S100A8-mediated NLRP3 inflammasome-dependent pyroptosis by TLR4/NF-κB activation and ROS production in macrophages facilitates liver fibrosis progression. The identified GSDMD has the potential to be a biomarker for liver fibrosis evaluation.
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Project description:Objective: Diabetes mellitus is a chronic progressive inflammatory metabolic disease with pancreatic β-cells dysfunction. The present study aimed to investigate whether miR-17-5p plays a protective effect on pancreatic β-cells function in diabetes mellitus (DM) mice and dissect the underlying mechanism. Methods: C57BL/6J mice were randomly divided into control, DM, DM + Lentivirus negative control (LV-NC), and DM + Lenti-OE™ miR-17-5p (LV-miR-17-5) groups. DM was established by feeding a high-fat diet and intraperitoneal injection with streptozotocin (STZ) in mice. Blood glucose and glucose tolerance in circulation were measured. Meanwhile, the activation of nod-like receptor protein 3 (NLRP3) inflammasome, pancreas pyroptosis, and the expression of miR-17-5p and thioredoxin-interacting protein (TXNIP) were detected in the pancreas of DM mice. Pancreatic β-cell line INS-1 subjected to different concentrations of glucose was used in in vitro experiments. Results: Compared with control mice, glucose tolerance deficit, elevated blood glucose level, and decreased pancreatic islet size, were presented in DM mice, which was associated with a downregulation of miR-17-5p. Importantly, exogenous miR-17-5p alleviated pancreas injury, and consequently improved glucose tolerance and decreased blood glucose in DM mice. In vitro experiments showed that high glucose decreased miR-17-5p expression and impaired insulin secretion in INS-1 cells. Mechanistically, miR-17-5p inhibited the expression of TXNIP and NLRP3 inflammasome activation, and thus decreased pancreatic β-cell pyroptosis. Conclusion: Our results demonstrated that miR-17-5p improves glucose tolerance, and pancreatic β-cell function and inhibits TXNIP/NLRP3 inflammasome pathway-related pyroptosis in DM mice.
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Project description:For more than 3 decades, mounting evidence has associated porcine reproductive and respiratory syndrome virus (PRRSV) infection with late-term abortions and stillbirths in sows and respiratory disease in piglets, causing enormous economic losses to the global swine industry. However, to date, the underlying mechanisms of PRRSV-triggered cell death have not been well clarified, especially in the pulmonary inflammatory injury characterized by the massive release of pro-inflammatory factors. Here, we demonstrated that PRRSV infection triggered gasdermin D-mediated host pyroptosis in vitro and in vivo. Mechanistically, PRRSV infection triggered disassembly of the trans-Golgi network (TGN); the dispersed TGN then acted as a scaffold for NLRP3 activation through phosphatidylinositol-4-phosphate. In addition, PRRSV replication-transcription complex (RTC) formation stimulated TGN dispersion and pyroptotic cell death. Furthermore, our results indicated that TMEM41B, an endoplasmic reticulum (ER)-resident host protein, functioned as a crucial host factor in the formation of PRRSV RTC, which is surrounded by the intermediate filament network. Collectively, these findings uncover new insights into clinical features as previously unrecognized mechanisms for PRRSV-induced pathological effects, which may be conducive to providing treatment options for PRRSV-associated diseases and may be conserved during infection by other highly pathogenic viruses. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the pathogens responsible for major economic losses in the global swine industry. Characterizing the detailed process by which PRRSV induces cell death pathways will help us better understand viral pathogenesis and provide implications for therapeutic intervention against PRRSV. Here, we showed that PRRSV infection induces GSDMD-driven host pyroptosis and IL-1β secretion through NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in vitro and in vivo. Furthermore, the molecular mechanisms of PRRSV-induced NLRP3 inflammasome activation and pyroptosis are elucidated here. The dispersed trans-Golgi network (TGN) induced by PRRSV serves as a scaffold for NLRP3 aggregation into multiple puncta via phosphatidylinositol 4-phosphate (PtdIns4P). Moreover, the formation of PRRSV replication-transcription complex is essential for TGN dispersion and host pyroptosis. This research advances our understanding of the PRRSV-mediated inflammatory response and cell death pathways, paving the way for the development of effective treatments for PRRSV diseases.
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Project description:Poly(ADP-ribose) polymerase-1 (PARP-1) plays an essential role in DNA repair by catalyzing the polymerization of ADP-ribose unit to target proteins. Several studies have shown that PARP-1 can regulate inflammatory responses in various disease models. The intracellular Nod-like receptor NLRP3 has emerged as the most crucial innate immune receptor because of its broad specificity in mediating immune response to pathogen invasion and danger signals associated with cellular damage. In our study, we found NLRP3 stimuli-induced caspase-1 maturation and IL-1β production were impaired by PARP-1 knockout or PARP-1 inhibition in bone marrow-derived macrophages (BMDM). The step 1 signal of NLRP3 inflammasome activation was not affected by PARP-1 deficiency. Moreover, ATP-induced cytosolic ROS production was lower in Parp-1-/- BMDM, resulting in the decreased inflammasome complex assembly. PARP-1 can translocate to cytosol upon ATP stimulation and trigger the PARylation modification on NLRP3, leading to NLRP3 inflammasome assembly. PARP-1 was also a bridge between NLRP3 and thioredoxin-interacting protein (TXNIP) and participated in NLRP3/TXNIP complex formation for inflammasome activation. Overall, PARP-1 positively regulates NLRP3 inflammasome activation via increasing ROS production and interaction with TXNIP and NLRP3, leading to PARylation of NLRP3. Our data demonstrate a novel regulatory mechanism for NLRP3 inflammasome activation by PARP-1. Therefore, PARP-1 can serve as a potential target in the treatment of IL-1β associated inflammatory diseases.
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Project description:Mycobacterium bovis is a facultative intracellular bacterium that produces cellular necrosis in granulomatous lesions in bovines. Although M. bovis-induced inflammation actively participates in granuloma development, its role in necrotic cell death and in bovine macrophages has not been fully explored. In this study, we evaluate the effect of M. bovis AN5 and its culture filtrate protein extract (CFPE) on inflammasome activation in bovine macrophages and its consequences on cell death. Our results show that both stimuli induce necrotic cell death starting 4 h after incubation. CFPE treatment and M. bovis infection also induce the maturation of IL-1β (>3000 pg/mL), oligomerization of ASC (apoptosis-associated speck-like protein containing CARD), and activation of caspase-1, following the canonical activation pathway of the NLRP3 inflammasome. Inhibiting the oligomerization of NLRP3 and caspase-1 decreases necrosis among the infected or CFPE-stimulated macrophages. Furthermore, histological lymph node sections of bovines naturally infected with M. bovis contained cleaved gasdermin D, mainly in macrophages and giant cells within the granulomas. Finally, the induction of cell death (apoptosis and pyroptosis) decreased the intracellular bacteria count in the infected bovine macrophages, suggesting that cell death helps to control the intracellular growth of the mycobacteria. Our results indicate that M. bovis induces pyroptosis-like cell death that is partially related to the NLRP3 inflammasome activation and that the cell death process could control bacterial growth.
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Project description:The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.
| S-EPMC8614891 | biostudies-literature
Project description:NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3' UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.
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