TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling

JHEP Reports, Journal Year: 2023, Volume and Issue: 5(5), P. 100695 - 100695

Published: Feb. 3, 2023

Oxidative stress-mediated ferroptosis and macrophage-related inflammation play an important role in various liver diseases. Here, we explored if how hepatocyte regulates macrophage stimulator of interferon genes (STING) activation the development spontaneous damage, fibrosis, tumorigenesis.We used a transforming growth factor-beta-activated kinase 1 (TAK1) deficiency-induced model tumorigenesis to investigate its impact on STING signalling. Primary hepatocytes macrophages were for vitro experiments.Significant injury increased numbers intrahepatic M1 found hepatocyte-specific TAK1-deficient (TAK1ΔHEP) mice, peaking at 4 weeks gradually decreasing 8 12 weeks. Meanwhile, signalling was observed livers from TAK1ΔHEP mice had decreased Treatment with inhibitor promoted M2 polarisation alleviated injury, tumour burden. TAK1 deficiency exacerbated iron metabolism high-iron diet. Moreover, consistent results single-cell RNA-Seq dataset, demonstrated oxidative response hepatocellular ferroptosis, which could be inhibited by reactive oxygen species scavenging. Suppression ferrostatin-1 signalling, leading attenuated fibrosis reduced Mechanistically, serum levels 8-hydroxydeoxyguanosine detected suppressed inhibition. antibody mice.Hepatocellular ferroptosis-derived DNA damage promotes facilitate tumorigenesis. Inhibition may represent novel therapeutic approach prevention chronic disease.The precise mechanism progression remains unclear. Herein, show that deletion caused carcinoma.

Language: Английский

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Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

Advanced Science, Journal Year: 2023, Volume and Issue: 10(26)

Published: July 12, 2023

In recent years, the incidence of gastrointestinal cancers is increasing, particularly in younger population. Effective treatment crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role growth and development organisms. It also critical maintaining tissue organ homeostasis takes part multiple pathological processes. addition to apoptosis, there are other types programmed such as ferroptosis, necroptosis, pyroptosis, which can induce severe inflammatory responses. Notably, besides pyroptosis contribute occurrence cancers. This review aims provide comprehensive summary on biological roles molecular mechanisms well their regulators hope open up new paths tumor targeted therapy near future.

Language: Английский

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Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps

Burns & Trauma, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 1, 2024

Abstract Background Ensuring the survival of distal end a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention programmed cell death potential strategy for inhibiting ischaemic necrosis. The activation stimulator interferon genes (STING) pathway promotes inflammation and leads to death. epidermal growth factor family member neuregulin-1 (NRG1) reduces by activating protein kinase B (AKT) signalling pathway. Moreover, AKT negatively regulates STING activity. We aimed verify efficacy NRG1 injection protecting against Additionally, we investigated whether effectively enhances ischemic pyroptosis necroptosis through suppression. Methods A random-pattern skin model was generated on backs C57BL/6 mice. area determined. blood supply vascular network assessed laser Doppler flow analysis. Cluster differentiation 34 immunohistochemistry (IHC) haematoxylin eosin (H&E) staining sections revealed microvessels. Transcriptome sequencing analysis mechanism which flaps. levels angiogenesis, oxidative stress, necroptosis, indicators associated with pathways flaps were examined IHC, immunofluorescence Western blotting. Packaging adeno-associated virus (AAV) used activate Results promoted An increased subcutaneous neovascularization found after application NRG1. Transcriptomic gene ontology enrichment level detection indicated that activity reduced group. phosphorylation forkhead box O3a (FOXO3a) treatment. expression induced AAV reversed therapeutic effect ability phosphorylate AKT-FOXO3a, inhibit promote abolished inhibitor MK2206. Conclusions inhibits AKT-FOXO3a suppress survival.

Language: Английский

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The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

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TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 22, 2025

Abnormality in transactivating response region DNA binding protein 43 (TDP43) is well-recognized as the pathological hallmark of neurodegenerative diseases. However, role TDP43 neuromyelitis optica spectrum disorder (NMOSD) remains unknown. Here, our observations demonstrate an upregulation both vitro and vivo models NMOSD, well biological samples from NMOSD patients. Single-nucleus RNA sequencing revealed that induced A1-like reactive astrocytes astrocyte mitochondrial dysfunction mice. We further found provoked translocation to mitochondria release (mtDNA) into cytoplasm. caused activation mtDNA/cyclic GMP-AMP synthase (cGAS) / stimulator interferon genes (STING) pathway A1-type inflammatory astrocytes. Crucially, knockdown markedly ameliorated NMOSD-induced cGAS/STING Conversely, overexpression exacerbated these changes. Specific silencing astrocytic injury mice, conversely, intensified injury. Meanwhile, cGAS STING inhibitors attenuated In summary, data suggest exacerbates through upregulating mtDNA/cGAS/STING signaling pathway. Therefore, targeting represents a compelling therapeutic strategy for NMOSD.

Language: Английский

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Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Dec. 13, 2022

Subarachnoid haemorrhage (SAH) is a common cerebrovascular disease with high disability and mortality rates worldwide. The pathophysiological mechanisms involved in an aneurysm rupture SAH are complex can be divided into early brain injury delayed injury. initial mechanical insult results tissue vascular disruption hemorrhages neuronal necrosis. Following this, the secondary diffused cerebral damage peri-core area. However, molecular of death following aneurysmal currently unclear. Furthermore, multiple cell pathways stimulated during pathogenesis damage. Notably, particular attention should devoted to necrosis, apoptosis, autophagy, necroptosis, pyroptosis ferroptosis. Thus, this review discussed mechanism its influence on after SAH.

Language: Английский

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STING mediates microglial pyroptosis via interaction with NLRP3 in cerebral ischaemic stroke

Stroke and Vascular Neurology, Journal Year: 2023, Volume and Issue: 9(2), P. 153 - 164

Published: July 3, 2023

Background Ischaemia-evoked neuroinflammation is a critical pathogenic event following ischaemic stroke. Gasdermin D (GSDMD)-associated pyroptosis represents type of inflammation-associated programmed cell death, which can exacerbate neuroinflammatory responses and brain damage. Stimulator interferon genes (STING) was recently described as vital innate immune adaptor protein associated with neuroinflammation. Nevertheless, the regulatory effects STING on microglial post-stroke have not been well elaborated. Methods STING-knockout wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO). small interfering RNA (siRNA) transfected into BV2 cells before oxygen-glucose deprivation/reoxygenation (OGD/R). STING-overexpressing adeno-associated virus (AAV) NOD-like receptor family pyrin domain containing 3 (NLRP3) siRNA administered by stereotaxic injection. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) Fluoro-Jade C (FJC) neurobehavioural tests, immunohistochemistry, cytokine antibody array assay, transmission electron microscopy, immunoblot, Enzyme-linked immunosorbent assay (ELISA) quantitative real-time polymerase chain reaction (qRT-PCR) carried out. Co-immunoprecipitation assays used investigate interplay between NLRP3. Results expression increased after MCAO mainly detected microglia. deletion alleviated infarction, neuronal damage impairment in MCAO. knockout suppressed activation secretion inflammatory chemokines, accompanied mitigation pyroptosis. Specific upregulation AAV-F4/80-STING aggravated injury Mechanistically, co-immunoprecipitation showed that bound NLRP3 Supplementation reversed AAV-F4/80-STING-induced deterioration Conclusions The current findings indicate modulates NLRP3-mediated may serve therapeutic target induced ischaemic/reperfusion (I/R) injury.

Language: Английский

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Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 1154 - 1154

Published: April 11, 2023

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number TBI survivors, impact and awareness this problem are growing. The mechanisms by which increases disease, however, not completely understood. a result, there no protective treatments for patients. Here, we review current literature surrounding epidemiology potential mechanistic relationships between In addition to increasing all forms dementia, most prominent conditions that accelerated amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), Alzheimer's (AD), with ALS FTD being least well-established. Mechanistic links reviewed include oxidative stress, dysregulated proteostasis, neuroinflammation. Disease-specific TAR DNA binding protein 43 motor cortex lesions FTD; alpha-synuclein, dopaminergic cell death, synergistic toxin exposure PD; insulin resistance, amyloid beta pathology, tau pathology AD. While compelling have been identified, expanded investigation field is needed develop therapies protect

Language: Английский

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Ursodeoxycholic acid alleviates sepsis-induced lung injury by blocking PANoptosis via STING pathway

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 125, P. 111161 - 111161

Published: Nov. 9, 2023

Language: Английский

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Ficolin B secreted by alveolar macrophage exosomes exacerbates bleomycin-induced lung injury via ferroptosis through the cGAS-STING signaling pathway

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(8)

Published: Aug. 30, 2023

Pathogenesis exploration and timely intervention of lung injury is quite necessary as it has harmed human health worldwide for years. Ficolin B (Fcn B) a recognition molecule that can recognize variety ligands play an important role in mediating the cell cycle, immune response, tissue homeostasis lung. However, Fcn bleomycin (BLM)-induced obscure. This study aims to investigate sources its mechanism BLM-induced injury. WT, Fcna-/-, Fcnb-/- mice were selected construct model. Lung epithelial cells utilized Exosomes secreted from alveolar macrophages (AMs) applied by transporting B. Clinical data suggested M-ficolin (homologous was raised plasma interstitial disease (ILD) patients. In mouse model, macrophage-derived aggravated fibrosis. further promoted development autophagy ferroptosis. Remarkably, experiment results revealed transported AMs exosomes accelerated ferroptosis through activation cGAS-STING pathway. contrast, application 3-Methyladenine (3-MA) reversed promotion effect on damage inhibiting autophagy-dependent Meanwhile, facilitated fibrosis via summary, this demonstrated exacerbated promoting signaling

Language: Английский

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