Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Clinical and Translational Medicine, Journal Year: 2020, Volume and Issue: 10(7)

Published: Nov. 1, 2020

Language: Английский

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Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(2), P. 129 - 142

Published: Feb. 1, 2022

Abstract Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as damage-associated molecular pattern (DAMP) monitored cGAS-STING axis to trigger immune response many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis type programmed promotes chronic tissue degeneration. However, relationship between inflammasome-induced pathogenesis IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) histopathology demonstrate cGAS, STING, are associated degree Oxidative stress induced activation inflammasome-mediated STING-dependent manner human cells. Interestingly, canonical morphological functional characteristics mitochondrial permeability transition pore (mPTP) opening escape (mtDNA) were observed cells under oxidative stress. Furthermore, administration specific pharmacological inhibitor mPTP self-mtDNA leakage effectively reduced pyroptotic microenvironmental inflammation vitro progression rat needle puncture model. Collectively, these data highlight critical roles cGAS-STING-NLRP3 provide promising therapeutic approaches for discogenic LBP.

Language: Английский

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Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Feb. 2, 2022

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As form of iron hydroperoxide-dependent regulated cell death, ferroptosis plays critical role sepsis-induced acute lung injury (ALI). However, the relationship between itaconate remains unclear. This study aims explore regulatory on ALI. In vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h generate experimental sepsis models. Differential gene expression analysis indicated that genes associated existed significant differences after pretreatment. 4-octyl (4-OI), cell-permeable derivative endogenous itaconate, can significantly alleviate injury, increase LPS-induced levels glutathione peroxidase 4 (GPX4) reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), ROS. vitro experiments showed both 4-OI ferrostatin-1 inhibited peroxidation THP-1 macrophage. Mechanistically, we identified GPX4-dependent through increased accumulation activation Nrf2. The silence Nrf2 abolished inhibition from cells. Additionally, protection ALI was Nrf2-knockout mice. We concluded one mechanisms contributing Itaconate is promising as therapeutic candidate against inhibiting ferroptosis.

Language: Английский

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Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 10, 2022

Neuroinflammation-induced injury is intimately associated with poor prognosis in patients cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) axis a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as crucial mediator neuroinflammation ischemic stroke. However, the role cGAS-STING modulating post-CVST inflammation and underlying mechanisms involved remain unclear.A CVST model was induced by ferric chloride male C57BL/6J mice. selective cGAS inhibitor RU.521, STING agonist 2'3'-cGAMP, siRNA were delivered intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C dihydroethidium western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA flow cytometry.cGAS, STING, NLRP3 GSDMD significantly upregulated after mostly microglia mouse brain. triggered release dsDNA into cytoplasm elicited an inflammatory response via activating axis. RU.521 decreased levels downstream cytokines, suppressed expressions inflammasome pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- IL-1β, IL-1β/pro-IL-1β. Besides, treatment also reduced oxidative stress, lessened numbers neutrophils, ameliorated neuronal apoptosis, degeneration along neurological deficits post-CVST. 2'3'-cGAMP delivery enhanced related mediators, pyroptosis-relevant proteins, whereas these alterations abrogated silencing siRNA.Our data demonstrate that repression diminishes neuroinflammatory burden highlight this approach potential therapeutic tactic CVST-mediated pathologies.

Language: Английский

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The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 13, 2022

Cyclic guanosine monophosphate (GMP)-adenosine (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components innate immune system, and their study has become a research hotspot in recent years. Many biochemical structural studies that have collectively elucidated mechanism activation cGAS-STING pathway atomic resolution provided insights into roles immunity clues to origin evolution modern signaling pathway. The been identified protect host against viral infection. After detecting dsDNA, cGAS synthesizes second messenger activate STING, eliciting antiviral responses by promoting expression interferons (IFNs) hundreds IFN-stimulated (ISGs). Recently, also found be involved response bacterial infections, including pneumonia, melioidosis, tuberculosis, sepsis. However, compared its functions infection, infection is more complex diverse since protective detrimental effects type I IFN (IFN-I) on depend species mode. Besides, STING can affect prognosis through other mechanisms different independent IFN-I response. Interestingly, core protein mammalian defense suggesting this widespread may originated bacteria. Here, we review findings related structures major molecules various infections immunity, which pave way for development new antibacterial drugs specifically kill bacteria without harmful host.

Language: Английский

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Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

Aging Cell, Journal Year: 2022, Volume and Issue: 21(6)

Published: May 22, 2022

Abstract Macrophage‐stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age‐related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING aged macrophages remains largely unknown. We found that hypoxia‐reoxygenation (HR) induced activation by triggering the release mtDNA into cytosol. Aging promoted cytosolic leakage enhanced activation, which was abrogated upon depletion or cyclic GMP‐AMP Synthase (cGAS) inhibition. Aged exhibited increased injury with impaired mitophagy. Mechanistically, a decline PTEN‐induced kinase 1 (PINK1)/Parkin‐mediated polyubiquitination mitochondria observed macrophages. Pink1 overexpression reversed inhibition ubiquitination but failed to promote mitolysosome formation Meanwhile, aging lysosomal biogenesis function modulating mTOR/transcription factor EB (TFEB) pathway, could be Torin‐1 treatment. Consequently, combination treatment restored mitophagic flux inhibited mtDNA/cGAS/STING Moreover, besides HR‐induced metabolic stress, other types oxidative hepatotoxic stresses mitophagy activate deficiency protected mice against diverse inflammatory liver injuries. Our findings suggest impairs facilitate cytosol promotes thereby provides novel potential therapeutic target for patients.

Language: Английский

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Garlic exosome-like nanoparticles reverse high-fat diet induced obesity via the gut/brain axis

Theranostics, Journal Year: 2022, Volume and Issue: 12(3), P. 1220 - 1246

Published: Jan. 1, 2022

Background: Obesity is becoming a global epidemic and reversing the pathological processes underlying obesity metabolic co-morbidities challenging.Obesity induced chronic inflammation including brain hallmark of via gut-brain axis.The objective this study was to develop garlic exosome-like nanoparticles (GaELNs) that inhibit systemic as well inflammatory activity reverse HFD in mice.Methods: GELNs were isolated administrated orally into fed mice.GaELNs fluorescent labeled for monitoring their vivo trafficking route after oral administration quantified number particles several tissues.The determined by measuring cytokines ELISA real-time PCR.Mitochondrial membrane permeability microglial cells using JC-10 fluorescence dye.The apoptotic cell death TUNEL assay.The metabolites identified LC-MS analysis.Memory function mice memory functional analysis.The effect GaELNs on glucose insulin response tolerance tests.c-Myc localization interaction with BASP1 calmodulin confocal microscopy.Results: Our results show preferentially taken up inhibits mice.GaELN phosphatidic acid (PA) (36:4) required uptake BASP1.Formation GaELNs/BASP1 complex inhibition c-Myc mediated expression STING.GaELN PA binds BASP1, leading through competitively binding CaM transcription factor.Inhibition STING leads reducing an array IFN-γ TNF-α.IFN-γ induces IDO1, which turn generated IDO1 dependent manner activate AHR pathway contributes developing obesity.The derived from treated promote neuronal differentiation mitochondrial death.GaELNs showed improved increased sensitivity these mice.Conclusion: Collectively, demonstrate how healthy diet can unhealthy high-fat reveal link between microglia/diet disease outcomes diet-derived nanoparticles.

Language: Английский

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Commensal cow Roseburia reduces gut-dysbiosis-induced mastitis through inhibiting bacterial translocation by producing butyrate in mice

Cell Reports, Journal Year: 2022, Volume and Issue: 41(8), P. 111681 - 111681

Published: Nov. 1, 2022

Highlights•Gut dysbiosis contributes to the development of mastitis and mammary dysbiosis•Bacterial translocation is involved in gut-dysbiosis-induced mastitis•Commensal Roseburia alleviates by producing butyrate•Butyrate improves barrier integrity limits bacterial translocationSummaryThe precise mechanism which gut pathogenesis extraintestinal diseases how commensal microbes mediate these processes remain unclear. Here, we show that cows with had marked dysbiosis, characterized enrichment opportunistic pathogenic Escherichia_Shigella depletion Roseburia. Fecal microbiota transplantation from donor (M-FMT) recipient mice significantly caused changed mice. Notably, M-FMT facilitated pathobiont into gland, Enterobacteriaceae alleviated M-FMT-induced In contrast, intestinalis improved microbial gland limited butyrate, was associated inflammatory signaling inhibition repair. Our research suggests mastitis, although further studies dairy humans are needed.Graphical abstract

Language: Английский

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Endoplasmic reticulum stress-induced NLRP3 inflammasome activation as a novel mechanism of polystyrene microplastics (PS-MPs)-induced pulmonary inflammation in chickens

Journal of Zhejiang University SCIENCE B, Journal Year: 2024, Volume and Issue: 25(3), P. 233 - 243

Published: March 1, 2024

Language: Английский

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cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 9, 2024

Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.

Language: Английский

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