XBP1-mediated activation of the STING signalling pathway in macrophages contributes to liver fibrosis progression

JHEP Reports, Год журнала: 2022, Номер 4(11), С. 100555 - 100555

Опубликована: Авг. 18, 2022

XBP1 modulates the macrophage proinflammatory response, but its function in stimulator of interferon genes (STING) activation and liver fibrosis is unknown. X-box binding protein 1 (XBP1) has been shown to promote nucleotide-binding oligomerization domain, leucine-rich repeat pyrin domain-containing 3 (NLRP3) steatohepatitis. Herein, we aimed explore underlying mechanism regulation STING signalling subsequent NLRP3 during fibrosis.XBP1 expression was measured human fibrotic tissue samples. Liver induced myeloid-specific Xbp1-, STING-, Nlrp3-deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet.Although increased observed macrophages clinical patients, Xbp1 deficiency pharmacological inhibition protected against fibrosis. Furthermore, it inhibited NLPR3 STING/IRF3-dependent manner. Oxidative mitochondrial injury facilitated cytosolic leakage self-mtDNA cGAS/STING/NLRP3 Mechanistically, RNA sequencing analysis indicated decreased mtDNA an BCL2/adenovirus E1B interacting (BNIP3)-mediated mitophagy Xbp1-deficient macrophages. Chromatin immunoprecipitation (ChIP) assays further suggested that spliced bound directly Bnip3 promoter transcription release STING/NLRP3 promoting BNIP3-mediated macrophages, which abrogated knockdown. Moreover, XBP1/STING contributed hepatic stellate cells.Our findings demonstrate controls regulating via modulation, thus providing novel target fibrosis.Liver typical progressive process chronic disease, driven inflammatory immune responses, characterised excess extracellular matrix liver. Currently, there no effective therapeutic strategy for treatment fibrosis, resulting high mortality worldwide. In this study, found mice, while ameliorated mice. This study concluded targeting may provide protecting

Язык: Английский

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Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Frontiers in Pharmacology, Год журнала: 2021, Номер 12

Опубликована: Дек. 23, 2021

Background: Acute lung injury (ALI) is characterized by dysfunction of the alveolar epithelial membrane caused acute inflammation and tissue injury. Qingwenzhike (QWZK) prescription has been demonstrated to be effective against respiratory viral infections in clinical practices, including coronavirus disease 2019 (COVID-19) infection. So far, chemical compositions, protective effects on ALI, possible anti-inflammatory mechanisms remain unknown. Methods: In this study, compositions QWZK were determined via linear ion trap/electrostatic field orbital trap tandem high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap MS). To test an ALI model induced lipopolysaccharide (LPS) rats was used. The LPS-induced evaluated pathological changes number classification white blood cell (WBC) bronchoalveolar lavage fluid (BALF). investigate underlying mechanisms, contents interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), interleukin-1β (IL-1β), interleukin-18 (IL-18), immunoregulatory-related factors interferon-γ (IFN-γ) detected ELISA. Furthermore, expression Toll-like receptor 4 (TLR4), p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-NF-κB, nuclear factor-κB (NF-κB), NOD-like family pyrin domain containing 3 (NLRP3), cleaved caspase-1, pro-caspase-1, apoptosis-associated speck-like CARD (ASC), β-actin tested Western blot. Results: A total 99 compounds identified QWZK, 33 flavonoids, 23 phenolic acids, alkaloids, coumarins, 20 triterpenoids, 5 anthraquinones, 12 others. LPS exhibited significant increase neutrophile, decrease lymphocyte, evidently thicker wall than control animals. reversed WBC count normal level LPS. ELISA results revealed that significantly reduced overexpression proinflammatory IL-6, TNF-α, MCP-1, IL-1β, IL-18, IFN-γ blot downregulated TLR4, NLRP3, ASC LPS, which suggested inhibited TLR4/NF-κB signaling pathway NLRP3 inflammasomes. Conclusions: first identified. It showed inhibiting TLR4/NF-kB inflammasome activation. This work a potential therapeutic candidate for treatments pulmonary inflammation.

Язык: Английский

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ICA69 aggravates ferroptosis causing septic cardiac dysfunction via STING trafficking

Cell Death Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Апрель 9, 2022

Previous studies have demonstrated that cardiomyocyte apoptosis, ferroptosis, and inflammation participate in the progress of sepsis-induced cardiomyopathy (SIC). Although Islet cell autoantigen 69 (ICA69) is an imperative molecule could regulate immune response numerous illnesses, its function cardiovascular disease, particularly SIC, still elusive. We confirmed LPS significantly enhanced expression ICA69 wild-type (WT) mice, macrophages, cardiomyocytes. The knockout lipopolysaccharide(LPS)-induced mice markedly elevated survival ratio heart function, while inhibiting cardiac muscle serum inflammatory cytokines, reactive oxygen (ROS), ferroptosis biomarkers. Mechanistically, increased triggered production STING, which further resulted intracellular lipid peroxidation, eventually triggering injury. Intriguingly, deficiency only reversed ferroptotic marker levels, such as prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), 4-hydroxynonenal (4HNE), glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), iron ROS, but had no effects on xCT-dependent manner. Additionally, greater level was identified septic patients peripheralblood mononuclear cells (PBMCs) than normal control groups. Generally, we unveil can relieve LPS-induced murine hearts making targeting a potentially promising treatment method for SIC.

Язык: Английский

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4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway

International Immunopharmacology, Год журнала: 2023, Номер 118, С. 110104 - 110104

Опубликована: Март 31, 2023

Язык: Английский

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Ferroptosis, necroptosis, and pyroptosis in cancer: Crucial cell death types in radiotherapy and post-radiotherapy immune activation

Radiotherapy and Oncology, Год журнала: 2023, Номер 184, С. 109689 - 109689

Опубликована: Май 6, 2023

Язык: Английский

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