Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 6, 2022

Background Inflammatory cytokines have been considered to be significant factors contributing the development and progression of non-alcoholic fatty liver disease (NAFLD). However, role inflammatory in NAFLD remains inconclusive. Objective This study aimed evaluate association between NAFLD. Methods PubMed, Web Science, Cochrane Library, EMBASE databases were searched until 31 December 2021 identify eligible studies that reported cytokine with its subtypes. We pooled odds ratios (ORs) hazard risk (HRs) 95% confidence intervals (CIs) conducted heterogeneity tests. Sensitivity analysis for publication bias also carried out. Results The search identified 51 relevant investigated 19 different based on 36,074 patients 47,052 controls. results meta-analysis showed associations C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1) (ORs 1.41, 1.08, 1.50, 1.15 2.17, respectively). In contrast, we observed non-significant interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), transforming factor-β (TGF-β) Our CRP, IL-1β, TNF-α significantly associated steatohepatitis (NASH) hepatic fibrosis. Conclusions indicated increased IL‐1β, IL-6, TNF‐α, ICAM-1 concentrations risks These mediators may serve as biomarkers subjects expect provide new insights into aetiology well early diagnosis intervention.

Language: Английский

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STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome

Redox Biology, Journal Year: 2023, Volume and Issue: 62, P. 102691 - 102691

Published: March 29, 2023

The activation of stimulator interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these epigenetic regulation STING-NLRP3 axis hepatocyte during fibrosis remain unknown. STING NLRP3 inflammasome are activated fibrotic livers but suppressed by Sting knockout. knockout ameliorated hepatic pyroptosis, inflammation, fibrosis. In vitro, induces primary murine hepatocytes activating inflammasome. H3K4-specific histone methyltransferase WD repeat-containing 5 (WDR5) DOT1-like H3K79 (DOT1L) identified to regulate expression STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated methylation enhances regulatory transcription factor (IRF3) binding Nlrp3 promoter promotes STING-induced Moreover, hepatocyte-specific deletion downstream Gasdermin D (Gsdmd) attenuate RNA-sequencing metabolomics analysis show that oxidative stress metabolic reprogramming might participate NLRP3-mediated STING-NLRP3-GSDMD inhibition suppresses ROS generation. conclusion, this study describes a novel mechanism which STING-WDR5/DOT1L/IRF3-NLRP3 pathway inflammation

Language: Английский

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Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 26, 2023

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% the population and is leading cause cirrhosis hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) monocyte-derived act as key players in progression NAFLD. Caspases are family endoproteases that provide critical connections cell regulatory networks sense risk factors, control inflammation, mediate inflammatory death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) induce pyroptosis defends against bacterial pathogens invade cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 promote

Language: Английский

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The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 27, 2024

Inflammasome activation and pyroptotic cell death are known to contribute the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although underlying regulatory mechanisms remain poorly understood. Here we report that expression levels E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse upon I/R injury. Genetic ablation MARCH2 aggravated infarction cardiac dysfunction Single-cell RNA-seq analysis suggested loss prompted NLRP3 inflammasome cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found act a novel regulator MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS fostering recruitment NLRP3. directly interacts PGAM5 promote its K48-linked polyubiquitination proteasomal degradation, resulting reduced PGAM5-MAVS co-condensation, consequently inhibition cardiomyocyte pyroptosis. AAV-based re-introduction significantly ameliorated I/R-induced heart dysfunction. Altogether, our findings reveal mechanism where MARCH2-mediated ubiquitination negatively regulates PGAM5/MAVS/NLRP3 axis protect against pyroptosis

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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The gasdermin family: emerging therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Language: Английский

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Hepatic danger signaling triggers TREM2 ⁺ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 13, 2024

Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms MASH center on hepatocyte injury and the ensuing immune response within microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, substantial induction NASH-associated (NAMs) serves a hallmark Despite this, through which NAMs contribute to pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) NAM-specific factor that exacerbates progression mice. Hepatic MS4A7 expression was strongly induced mouse human associated with severity injury. Whole-body myeloid-specific ablation Ms4a7 alleviated diet-induced pathologies male We demonstrate exposure lipid droplets (LDs), released upon steatotic hepatocytes, triggered NAM exacerbated MASH-associated MS4A7-dependent manner. Mechanistically, drove NLRP3 inflammasome activation via direct physical interaction shaped disease-associated cell states This reveals LD-MS4A7-NLRP3 axis driver provides insights into role pathogenesis.

Language: Английский

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SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103159 - 103159

Published: April 16, 2024

The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance solute carrier family 7 member 11 (SLC7A11) metabolism. Nevertheless, whether SLC7A11 regulates through mediating is unclear. In this study, we found that expression was increased liver samples from patients with NASH. Upregulated level also detected murine models. Functional studies showed knockdown or knockout had augmented suppression inflammatory markers mice. overexpression dramatically alleviated diet-induced pathogenesis. Mechanically, decreased reactive oxygen species (ROS) promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, impaired NLRP3 inflammasome components AMPK-mitophagy axis. IL-1β release recruited myeloid cells hepatic stellate (HSCs) activation, contributed injury fibrosis. Anti-IL-1β anakinra might attenuate response evoked by knockdown. Moreover, upregulation lipid overload-induced JNK-c-Jun conclusions, acts as a protective factor controlling development Upregulation regulating oxidation, αKG energy metabolism, decreasing

Language: Английский

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Activation and evasion of inflammasomes during viral and microbial infection

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: Jan. 21, 2025

The inflammasome is a cytoplasmic multiprotein complex that induces the maturation of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) or pyroptosis by activating caspases, which play critical roles in regulating inflammation, cell death, various cellular processes. Multiple studies have shown key regulator host defence response against pathogen infections. During process pathogenic microbe invasion into cells, host's innate immune system recognizes these microbes inflammasomes, triggering inflammatory responses to clear initiate responses. Moreover, microbial pathogens evolved mechanisms inhibit evade activation inflammasomes. Therefore, we review interactions between viruses with inflammasomes during process, highlight molecular induced infection, corresponding strategies employ activity. Finally, also discuss potential therapeutic for treatment infections via targeting their products.

Language: Английский

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Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 25, 2022

Ovarian cancer (OC) is one of the most common malignancies that causes death in women and a heterogeneous disease with complex molecular genetic changes. Because relatively high recurrence rate OC, it crucial to understand associated mechanisms drug resistance discover potential target for rational targeted therapy. Cell genetically determined process. Active orderly cell prevalent during development living organisms plays critical role regulating life homeostasis. Ferroptosis, novel type discovered recent years, distinct from apoptosis necrosis mainly caused by imbalance between production degradation intracellular lipid reactive oxygen species triggered increased iron content. Necroptosis regulated non-cysteine protease–dependent programmed necrosis, morphologically exhibiting same features as occurring via unique mechanism different apoptotic signaling pathway. Pyroptosis form characterized formation membrane pores subsequent lysis well release pro-inflammatory contents mediated abscisin family. Studies have shown ferroptosis, necroptosis, pyroptosis are involved progression variety diseases, including tumors. In this review, we summarized advances occurrence, development, therapeutic OC.

Language: Английский

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