Inhibition of STAT3 phosphorylation by colchicine regulates NLRP3 activation to alleviate sepsis-induced acute lung injury

Liu, Yuanshui; Yang, Hang; Zhu, Faming; Ouyang, Yan‐Qiong; Pan, Pinhua

doi:10.1007/s10787-023-01199-9

Cited by 9 publications

(7 citation statements)

References 26 publications

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“… 45 , 46 Notably, recent research has increasingly focused on the influence of STAT3 on the progression of different diseases through the regulation of cell death, including sepsis and lung injury. 47 , 48 Additionally, certain studies have demonstrated that p-STAT3 facilitates the acetylation of histone H3 and H4 on the NLRP3 promoter, as well as the activation of the NLRP3 inflammasome, which may be directly regulated by p-STAT3. 48 Furthermore, several studies have demonstrated the impact of STAT3 on pyroptosis through its influence on other targets, including AIM2 and GSDME.…”

Section: Discussionmentioning

confidence: 99%

“… 47 , 48 Additionally, certain studies have demonstrated that p-STAT3 facilitates the acetylation of histone H3 and H4 on the NLRP3 promoter, as well as the activation of the NLRP3 inflammasome, which may be directly regulated by p-STAT3. 48 Furthermore, several studies have demonstrated the impact of STAT3 on pyroptosis through its influence on other targets, including AIM2 and GSDME. 49 , 50 Consequently, the modulation of STAT3 presents a promising therapeutic approach for mitigating sepsis-induced ARDS by suppressing macrophage pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

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Mitigation of Sepsis-Induced Acute Lung Injury by BMSC-Derived Exosomal miR-125b-5p Through STAT3-Mediated Suppression of Macrophage Pyroptosis

Tao,

Xu,

Yang

et al. 2023

IJN

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Introduction Sepsis is a syndrome characterized by high morbidity and mortality rates. One of its most severe complications is acute lung injury, which exhibits a multitude of clinical and biological features, including macrophage pyroptosis. This study investigates the regulatory effects of exosomes derived from Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs) on sepsis-associated acute lung injury (ALI) and explores the potential mechanisms mediated by exosomal miRNAs. Methods Exosomes were isolated from primary BMSCs of adult C57BL/6J mice using differential centrifugation. Their uptake and distribution in both in vitro and in vivo contexts were validated. Key sepsis-associated hub gene signal transducer and activator of transcription 3 (STAT3) and its upstream non-coding miR-125b-5p were elucidated through a combination of bioinformatics, machine learning, and miRNA sequencing. Subsequently, the therapeutic potential of BMSC-derived exosomes in alleviating sepsis-induced acute lung injury was substantiated. Moreover, the functionalities of miR-125b-5p and STAT3 were corroborated through miR-125b-5p inhibitor and STAT3 agonist interventions, employing gain and loss-of-function strategies both in vitro and in vivo. Finally, a dual-luciferase reporter assay reaffirmed the interaction between miR-125b-5p and STAT3. Results We isolated exosomes from primary BMSCs and confirmed their accumulation in the mouse lung as well as their uptake by macrophages in vitro. This study identified the pivotal sepsis-associated hub gene STAT3 and demonstrated that exosomes derived from BMSCs can target STAT3, thereby inhibiting macrophage pyroptosis. MiR-125b-5p inhibition experiments showed that exosomes mitigate macrophage pyroptosis and lung injury by delivering miR-125b-5p. STAT3 overexpression experiments validated that miR-125b-5p reduces macrophage pyroptosis and lung injury by suppressing STAT3. Furthermore, a dual-luciferase reporter assay confirmed the binding interaction between miR-125b-5p and STAT3. Conclusion Exosomes derived from BMSCs, serving as carriers for delivering miR-125b-5p, can downregulate STAT3, thereby inhibiting macrophage pyroptosis and alleviating sepsis-associated ALI. These significant findings provide valuable insights into the potential development of ALI therapies centred around exosomes derived from BMSC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitigation of Sepsis-Induced Acute Lung Injury by BMSC-Derived Exosomal miR-125b-5p Through STAT3-Mediated Suppression of Macrophage Pyroptosis

Tao,

Xu,

Yang

et al. 2023

IJN

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“…After the detection of RNA purity and concentration using the spectrophotometer (Thermo Fisher, Waltham, MA, USA), TransScript® Reverse Transcriptase [M-MLV, RNaseH-] (AT101-02, Transgen, Beijing, China) was used for the reverse transcription. The qPCR reactions were then performed on an ABI 7900HT Fast platform using the TransStart® Green qPCR SuperMix (AQ101-01, TransGen, Beijing, China) according to the manufacturer’s instructions 50 . The sequences of the forward and reverse primers were displayed in Table 1 (Tsingke Biotech, Beijing, China).…”

Section: Methodsmentioning

confidence: 99%

Exploration of the role of oxidative stress-related genes in LPS-induced acute lung injury via bioinformatics and experimental studies

Liu,

Li,

Ouyang

et al. 2023

Sci Rep

Self Cite

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During the progression of acute lung injury (ALI), oxidative stress and inflammatory responses always promote each other. The datasets analyzed in this research were acquired from the Gene Expression Omnibus (GEO) database. The Weighted Gene Co-expression Network Analysis (WGCNA) and limma package were used to obtain the ALI-related genes (ALIRGs) and differentially expressed genes (DEGs), respectively. In total, two biological markers (Gch1 and Tnfaip3) related to oxidative stress were identified by machine learning algorithms, Receiver Operator Characteristic (ROC), and differential expression analyses. The area under the curve (AUC) value of biological markers was greater than 0.9, indicating an excellent power to distinguish between ALI and control groups. Moreover, 15 differential immune cells were selected between the ALI and control samples, and they were correlated to biological markers. The transcription factor (TF)-microRNA (miRNA)-Target network was constructed to explore the potential regulatory mechanisms. Finally, based on the quantitative reverse transcription polymerase chain reaction (qRT-PCR), the expression of Gch1 and Tnfaip3 was significantly higher in ALI lung tissue than in healthy controls. In conclusion, the differences in expression profiles between ALI and normal controls were found, and two biological markers were identified, providing a research basis for further understanding the pathogenesis of ALI.

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“…NLRP3, an inflammation-associated protein, is a critical intracellular receptor predominantly in immune cells. It plays a pivotal role in inflammation and immune responses [ 47 ].…”

Section: Pathogenesis Of Sepsis-induced Ali and Potential Therapeutic...mentioning

confidence: 99%

“…In a subsequent study in 2023, Pan explored the protective effects of colchicine against LPS-induced lung injury and its underlying mechanisms. It was discovered that colchicine inhibits the phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which regulates the activation of NLRP3, thereby reducing the inflammatory response and apoptosis [ 47 , 48 ].…”

Section: Pathogenesis Of Sepsis-induced Ali and Potential Therapeutic...mentioning

confidence: 99%

Mechanisms of Sepsis-Induced Acute Lung Injury and Advancements of Natural Small Molecules in Its Treatment

Xu,

Xin,

Sun

et al. 2024

Pharmaceuticals

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Sepsis-induced acute lung injury (ALI), characterized by widespread lung dysfunction, is associated with significant morbidity and mortality due to the lack of effective pharmacological treatments available clinically. Small-molecule compounds derived from natural products represent an innovative source and have demonstrated therapeutic potential against sepsis-induced ALI. These natural small molecules may provide a promising alternative treatment option for sepsis-induced ALI. This review aims to summarize the pathogenesis of sepsis and potential therapeutic targets. It assembles critical updates (from 2014 to 2024) on natural small molecules with therapeutic potential against sepsis-induced ALI, detailing their sources, structures, effects, and mechanisms of action.

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Inhibition of STAT3 phosphorylation by colchicine regulates NLRP3 activation to alleviate sepsis-induced acute lung injury

Cited by 9 publications

References 26 publications

Mitigation of Sepsis-Induced Acute Lung Injury by BMSC-Derived Exosomal miR-125b-5p Through STAT3-Mediated Suppression of Macrophage Pyroptosis

Mitigation of Sepsis-Induced Acute Lung Injury by BMSC-Derived Exosomal miR-125b-5p Through STAT3-Mediated Suppression of Macrophage Pyroptosis

Exploration of the role of oxidative stress-related genes in LPS-induced acute lung injury via bioinformatics and experimental studies

Mechanisms of Sepsis-Induced Acute Lung Injury and Advancements of Natural Small Molecules in Its Treatment

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