STING regulates NETs formation by activating GSDMD in influenza viral pneumonia

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Publicat a:Frontiers in Immunology vol. 16 (Jul 2025), p. 1598902-1598921
Autor principal: Huang, Rongrong
Altres autors: Chen, Ranran, Xing, Lijuan, Wu, Lianhao, Zhu, Wenwen, Jing, Junsong, Zhou, Ting, Wu, Yueguo, Zhang, Sheng, You, Zhenqiang
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Frontiers Media SA
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022 |a 1664-3224 
024 7 |a 10.3389/fimmu.2025.1598902  |2 doi 
035 |a 3278302310 
045 2 |b d20250701  |b d20250731 
100 1 |a Huang, Rongrong  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
245 1 |a STING regulates NETs formation by activating GSDMD in influenza viral pneumonia 
260 |b Frontiers Media SA  |c Jul 2025 
513 |a Journal Article 
520 3 |a BackgroundViral pneumonia is the most common and lethal pandemic disease, but there are no broad-spectrum antiviral drugs with high genetic barriers to resistance. To elucidate the mechanisms of viral pneumonia progression and potential targets for its treatment.MethodsViral pneumonia models were induced by the PR8 virus strain in wild-type (WT) and STING knockout (STING-KO) mice. Series of molecular biology techniques were used to evaluate the severity of pneumonia and cytokine levels.ResultsIn this study, STING (stimulator of interferon genes) was activated in the lungs of virus-infected mice, leading to cytokine production and amplification of the immune response, thereby causing rapid deterioration of symptoms. Furthermore, excessive activation of innate immune response via STING was prevented by a STING inhibitor (C-176), which significantly reduced viral lung inflammation. The formation of neutrophil extracellular traps (NETs) was similarly suppressed during viral pneumonia treatment with STING inhibitors (C-176), and NETs formation and STING expression were positively correlated, indicating that STING plays an important role in NETs formation. Symptoms of pneumonia in STING-KO mice infected with PR8 were significantly milder than those in WT mice, and NETs were less likely to form in the lung tissue of STING-KO mice. Additionally, transcriptomic analysis revealed that STING-mediated regulation of NETs may be associated with gasdermin D (GSDMD), and immunoprecipitation experiments revealed that STING, GSDMD, and NETs-related proteins interact with each other. Immunofluorescence assays revealed that in neutrophils from WT mice, STING and GSDMD were colocalized on the membrane after viral infection, whereas in neutrophils from STING-KO mice, GSDMD expression was decreased after exposure to the virus.ConclusionsOur study demonstrated that targeted intervention with STING alleviated pneumonia by inhibiting inflammation and NETs formation. The study also revealed that blocking STING could inhibit the activation of GSDMD to inhibit NETs formation, slowing the progression of viral pneumonia. 
651 4 |a United States--US 
651 4 |a Shanghai China 
651 4 |a China 
653 |a Infections 
653 |a Pathogens 
653 |a Investigations 
653 |a Neutrophils 
653 |a Antibodies 
653 |a Accreditation 
653 |a Pneumonia 
653 |a Leukocytes (neutrophilic) 
653 |a Cytokines 
653 |a Innate immunity 
653 |a Influenza 
653 |a Inflammation 
653 |a Transcriptomics 
653 |a Kinases 
653 |a Antiviral agents 
653 |a Medical schools 
653 |a Laboratory animals 
653 |a Proteins 
653 |a Immune response 
653 |a Immunity (Disease) 
653 |a Immunofluorescence 
653 |a Autoimmune diseases 
653 |a Immunoprecipitation 
653 |a Respiratory distress syndrome 
653 |a Viruses 
653 |a Immunosuppressive agents 
653 |a Pathogenesis 
700 1 |a Chen, Ranran  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
700 1 |a Xing, Lijuan  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
700 1 |a Wu, Lianhao  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
700 1 |a Zhu, Wenwen  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China 
700 1 |a Jing, Junsong  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
700 1 |a Zhou, Ting  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China 
700 1 |a Wu, Yueguo  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China 
700 1 |a Zhang, Sheng  |u Center for Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China 
700 1 |a You, Zhenqiang  |u School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China, School of Public Health, Hangzhou Medical College, Hangzhou, China, Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, China 
773 0 |t Frontiers in Immunology  |g vol. 16 (Jul 2025), p. 1598902-1598921 
786 0 |d ProQuest  |t Health & Medical Collection 
856 4 1 |3 Citation/Abstract  |u https://www.proquest.com/docview/3278302310/abstract/embedded/L8HZQI7Z43R0LA5T?source=fedsrch 
856 4 0 |3 Full Text  |u https://www.proquest.com/docview/3278302310/fulltext/embedded/L8HZQI7Z43R0LA5T?source=fedsrch 
856 4 0 |3 Full Text - PDF  |u https://www.proquest.com/docview/3278302310/fulltextPDF/embedded/L8HZQI7Z43R0LA5T?source=fedsrch