STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury

Cell Death and Disease, Год журнала: 2024, Номер 15(3)

Опубликована: Март 14, 2024

Abstract Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged a critical component immune inflammatory responses. However, role STING in pathogenesis septic AKI remains unclear. This study demonstrated that was significantly activated tubular cells induced lipopolysaccharide (LPS) vivo vitro. Tubule-specific knockout attenuated LPS-induced renal dysfunction pathological changes. Mechanistically, pathway promotes NOD-like receptor protein 3 (NLRP3) activation. triggers endoplasmic reticulum (ER) stress induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting activation association with NLRP3. Eventually, NLRP3 inflammasome leads cell pyroptosis. revealed STING-regulated network further identified STING/ER stress/mtROS/NLRP3 axis an emerging contributing damage AKI. Hence, targeting may be promising therapeutic strategy preventing

Язык: Английский

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Macrophage STING signaling promotes fibrosis in benign airway stenosis via an IL6-STAT3 pathway

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Acute and chronic inflammation are important pathologies of benign airway stenosis (BAS) fibrosis, which is a frequent complication critically ill patients. cGAS-STING signalling has an role in yet the function STING BAS remains unclear. Here we demonstrate using scRNA sequencing that cGAS‒STING involved BAS, accompanied by increased dsDNA, expression activation STING. inhibition or deficiency effectively alleviates tracheal fibrosis mice decreasing both acute inflammation. Macrophage depletion also ameliorates BAS. Mechanistically, dsDNA from damaged epithelial cells activates pathway macrophages induces IL-6 to activate STAT3 promote fibrosis. In summary, present results suggest amplifies associated with stenosis, highlighting mechanism potential drug target Benign characterised trachea. authors examine mouse models show involvement macrophage ameliorated

Язык: Английский

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STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion

Acta Pharmacologica Sinica, Год журнала: 2021, Номер 43(8), С. 2055 - 2066

Опубликована: Дек. 14, 2021

Язык: Английский

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Pyroptosis-Induced Inflammation and Tissue Damage

Journal of Molecular Biology, Год журнала: 2021, Номер 434(4), С. 167301 - 167301

Опубликована: Окт. 13, 2021

Язык: Английский

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Melatonin protects against PM2.5-induced lung injury by inhibiting ferroptosis of lung epithelial cells in a Nrf2-dependent manner

Ecotoxicology and Environmental Safety, Год журнала: 2021, Номер 223, С. 112588 - 112588

Опубликована: Авг. 4, 2021

PM2.5 refers to ambient air particulate matter with aerodynamic diameters ≤ 2.5 µm, which has been a global environmental problem threatening public health in recent years. Melatonin serving as one of the predominant hormones secreted by pineal gland displays multiple pharmacological properties various diseases. However, little is known about possible effects melatonin development lung injury induced PM2.5. This study was designed explore potential roles well its mechanisms PM2.5-induced injury. In present study, mice were intratracheally instilled dissolved sterile water induce or without intragastric administration melatonin. The results showed that treatment significantly alleviated pathological and edema, apart from inhibiting inflammatory cell infiltration. Meantime, also decreased makers ferroptosis lipid peroxidation products tissues challenged Additionally, promoted nuclear translocation expression Nrf2 protein degradation Keap1. pulmonary protection anti-ferroptosis effect counteracted Nrf2-deficiency mice. vitro experiments further demonstrated knockdown could offset MLE-12 epithelial cells. Taken together, our disclosed relieve via cells activating Nrf2. Hence, may be promising candidate against associated matter.

Язык: Английский

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Inflammatory Caspases Drive Pyroptosis in Acute Lung Injury

Frontiers in Pharmacology, Год журнала: 2021, Номер 12

Опубликована: Фев. 5, 2021

Acute lung injury (ALI), a critical respiratory disorder that causes diffuse alveolar leads to high mortality rates with no effective treatment. ALI is characterized by varying degrees of ventilation/perfusion mismatch, severe hypoxemia, and poor pulmonary compliance. The cells one most important pathological characteristics ALI. Pyroptosis form programmed cell death distinguished from apoptosis induced inflammatory caspases, which can release cytokines clear infected pathogens promote monocytes reassemble at the site injury. And pyroptosis not only promotes inflammation in certain types, but also regulates many downstream pathways perform different functions. There increasing evidence its related caspases play an role development acute main modes activation consistent among types tissue. Meanwhile, inhibition inflammasome, key initiating currently way treat review summarizes relationship provides general directions strategies conduct further research.

Язык: Английский

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Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway

Clinical Science, Год журнала: 2022, Номер 136(4), С. 273 - 289

Опубликована: Фев. 1, 2022

Abstract Background: NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated macrophage pyroptosis plays an important role in sepsis-induced acute lung injury (ALI). Inhibition of may be a way to alleviate inflammation as well tissue damage triggered after lipopolysaccharide (LPS) stimulation. The aim the present study was explore whether buformin (BF), hypoglycemic agent, could ALI by inhibiting pyroptosis. Methods: Wildtype C57BL/6 mice were randomly divided into control group, BF LPS group and LPS+BF group. pretreated with at dose 25 mg/kg, changes observed. In addition, used interfere THP-1 cells. therapeutic effect has been verified intraperitoneal injection vivo Results: Inflammation significantly reduced mice, indexes related suppressed. phosphorylation AMP-activated protein kinase (AMPK) tissues groups higher. cells, AMPK inhibitor, Compound C added demonstrate that worked via inhibit NLRP3 inflammasome. It further demonstrated up-regulated autophagy, which turn promoted inflammasome degradation. On other hand, decreased mRNA level increasing nuclear factor-erythroid 2 factor (Nrf2). And showed challenge. Conclusion: Our confirmed inhibited NLRP3-mediated up-regulating autophagy Nrf2 through AMPK-dependent pathway. This provides new strategy for clinical mitigation ALI.

Язык: Английский

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Mitochondrial DNA in NLRP3 inflammasome activation

International Immunopharmacology, Год журнала: 2022, Номер 108, С. 108719 - 108719

Опубликована: Март 26, 2022

Язык: Английский

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Autophagy Regulation on Pyroptosis: Mechanism and Medical Implication in Sepsis

Mediators of Inflammation, Год журнала: 2021, Номер 2021, С. 1 - 11

Опубликована: Июнь 24, 2021

Sepsis is defined as a life-threatening disease involving multiple organ dysfunction caused by dysregulated host responses to infection. To date, sepsis remains dominant cause of death among critically ill patients. Pyroptosis unique form programmed cell mediated the gasdermin family proteins and causes lytic release proinflammatory cytokines. Although there might be some positive aspects pyroptosis, it regarded harmful during needs restricted. Autophagy was originally characterized homeostasis-maintaining mechanism in living cells. In past decade, its function negatively modulating pyroptosis inflammation has attracted increased attention. Here, we present comprehensive review regulatory effect autophagy on sepsis, including latest advances our understanding signaling pathways involved, well potential therapeutic application sepsis.

Язык: Английский

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PM2.5-induced lung injury is attenuated in macrophage-specific NLRP3 deficient mice

Ecotoxicology and Environmental Safety, Год журнала: 2021, Номер 221, С. 112433 - 112433

Опубликована: Июнь 17, 2021

Fine particulate matter (PM2.5) is one of the most important components environmental pollutants and associated with lung injury. Pyroptosis, a form programmed cell death mainly mediated by NLRP3 inflammasome, has been reported to be involved in sepsis-induced or ischemia/reperfusion-induced However, specific mechanisms pyroptosis PM2.5-induced injury are not yet clear. We constructed macrophage-specific knockout mice explore mechanism terms inflammatory response, oxidative stress, apoptosis levels, including relationship between these effects pyroptosis. The results disclosed that PM2.5 exposure increased infiltration macrophages leukocytes secretion cytokines, TNF-α IL-6, tissue. activity antioxidant enzymes, SOD, GSH-PX, CAT, significantly decreased, while MDA, end product lipid oxidation, remarkably increased. level tissue, measured TUNEL assay apoptosis-related proteins (BAX BCL-2), was Macrophage-specific could offset effects. further observed treatment activated inflammasome subsequently induced pyroptosis, as evidenced production IL-1β IL-18 increase protein levels NLRP3, ASC, caspase-1, GSDMD, which were inhibited when knocked out macrophages. Taken together, revealed NLRP3-mediated macrophage promoted through aggravating inflammation, apoptosis. Targeting inhibition provides new way study PM2.5.

Язык: Английский

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