Email Alerts
RSS
Volume 40 Issue 10
Oct.  2024
Turn off MathJax
Article Contents
Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  > 2024  >  40(10): 920-929
Wu MY,He PY,Duan Y,et al.Effects of stimulator of interferon gene on ferroptosis mediated by acyl-CoA synthetase long-chain family member 4 in mouse dendritic cells under sepsis[J].Chin J Burns Wounds,2024,40(10):920-929.DOI: 10.3760/cma.j.cn501225-20240518-00184.
Citation: Wu MY,He PY,Duan Y,et al.Effects of stimulator of interferon gene on ferroptosis mediated by acyl-CoA synthetase long-chain family member 4 in mouse dendritic cells under sepsis[J].Chin J Burns Wounds,2024,40(10):920-929.DOI: 10.3760/cma.j.cn501225-20240518-00184.
shu

Effects of stimulator of interferon gene on ferroptosis mediated by acyl-CoA synthetase long-chain family member 4 in mouse dendritic cells under sepsis

doi: 10.3760/cma.j.cn501225-20240518-00184
  • 1.

    Medical Innovation Research Division and the Fourth Medical Center of PLA General Hospital, Beijing 100853, China

  • 2.

    Department of General Surgery, the First Medical Center of PLA General Hospital, Beijing 100853, China

Funds:

Key Program of National Natural Science Foundation of China 82130062, 82241062

The Youth Independent Innovation Science Fund Support Project of PLA General Hospital 22QNFC017

More Information
  • Corresponding author: Yao Yongming, Email: c_ff@sina.com
  • Received Date: 2024-05-18
    Abstract
  •   Objective  To investigate the effects of stimulator of interferon gene (STING) on ferroptosis mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4) in mouse dendritic cells (DCs) under sepsis, providing a basis for improving the dysregulation of immune response in sepsis caused by factors such as wound infection.  Methods  This study was an experimental research. The mouse DC line DC2.4 in the logarithmic growth phase (with passages 3-10) were divided into lipopolysaccharide (LPS) stimulation 0 h (unstimulated) group, LPS stimulation 6 h group, LPS stimulation 12 h group, LPS stimulation 18 h group, and LPS stimulation 24 h group according to the random number table (the same grouping method below), which were cultured with 1 μg/mL LPS (the same concentration below) for the corresponding time. The protein expressions of phosphorylated STING (p-STING), STING, and ACSL4 in cells were determined by Western blotting. DC2.4 successfully transfected with lentivirus containing STING gene small interfering RNA (hereinafter referred to as siSTING) were divided into siSTING+phosphate buffer solution (PBS) group and siSTING+LPS group. DC2.4 successfully transfected with empty lentivirus were divided into empty vector+PBS group and empty vector+LPS group. After being stimulated with PBS or LPS and cultured for 24 hours, the protein expressions of p-STING, STING, and ACSL4 in cells were determined as above. Cell lipid peroxidation degrees were observed using the lipid peroxidation assay kit, and cell apoptosis rates were detected using flow cytometry. The sample numbers in the above cell experiments were all 3. Eighty male C57BL/6J mice aged 6 to 8 weeks were divided into sham surgery+normal saline (NS) group, cecal ligation and puncture (CLP)+NS group, sham surgery+C-176 group, and CLP+C-176 group, with 20 mice in each group. Mice in the two C-176 groups were intraperitoneally injected with C-176, while mice in the two NS groups were intraperitoneally injected with an equivalent volume of NS. One hour later, sham surgery was performed on the mice in the two sham surgery groups, and CLP surgery was performed on the mice in the two CLP groups to establish a sepsis model. At 24 h post-surgery, 10 mice from each group were sacrificed to extract spleen DCs, and protein expression, lipid peroxidation, and apoptosis rates were detected as above (n=3). Hematoxylin-eosin staining was performed to observe pathological damage in the heart, liver, lung, and kidney tissue. The remaining 10 mice in each group were observed for survival within 7 days after surgery.  Results  The protein expressions of p-STING, STING, and ACSL4, as well as the p-STING/STING ratio in DC2.4 in LPS stimulation 24 h group were significantly higher than those in LPS stimulation 0 h group (P<0.05). After 24 h of culture, the protein expressions of p-STING, STING, and ACSL4 in DC2.4 in siSTING+LPS group and empty vector+PBS group were significantly lower than those in empty vector+LPS group (P<0.05); the lipid peroxidation degrees of DC2.4 in siSTING+LPS group and empty vector+PBS group were weaker than those in empty vector+LPS group. The apoptosis rates of DC2.4 in empty vector+PBS group, empty vector+LPS group, siSTING+PBS group, and siSTING+LPS group were (15.7±3.0)%, (37.8±2.9)%, (13.1±2.1)%, and (20.6±1.8)%, respectively. The apoptosis rates of DC2.4 in empty vector+PBS group and siSTING+LPS group were significantly lower than that in empty vector+LPS group (P<0.05). At 24 h post-surgery, the protein expressions of p-STING and ACSL4, and the p-STING/STING ratio in spleen DCs of mice in CLP+NS group were significantly higher than those in sham surgery+NS group and CLP+C-176 group (P<0.05); the protein expression of STING in spleen DCs of mice in CLP+NS group was significantly higher than that in sham surgery+NS group (P<0.05); the lipid peroxidation degrees of spleen DCs of mice in CLP+C-176 group and sham surgery+NS group were weaker than that in CLP+NS group. The apoptosis rates of spleen DCs of mice in sham surgery+NS group and CLP+C-176 group were significantly lower than that in CLP+NS group (P<0.05), and the apoptosis rate of spleen DCs of mice in CLP+C-176 group was significantly higher than that in sham surgery+C-176 group (P<0.05). Pathological tissue damage in the heart, liver, lung, and kidney of mice in CLP+NS group was significantly worse than that in sham surgery+NS group, while such damage in the above organs of mice in CLP+C-176 group was significantly alleviated compared with that in CLP+NS group. The survival ratio of mice in CLP+NS group within 7 days after surgery was significantly lower than that in sham surgery+NS group (χ2=8.30, P<0.05).  Conclusions  Under sepsis, STING activation in mouse DCs is significant, which enhances ACSL4-mediated ferroptosis. Inhibiting STING activation can significantly reduce ACSL4-mediated ferroptosis level in mouse DCs under sepsis, thereby improving the survival rate of septic mice.

     

    • FullText(HTML)
  • loading
    • References(30)
  • [1]
    GaoKM, Marshak-RothsteinA, FitzgeraldKA. Type-1 interferon-dependent and -independent mechanisms in cyclic GMP-AMP synthase-stimulator of interferon genes-driven auto-inflammation[J]. Curr Opin Immunol, 2023, 80:102280. DOI: 10.1016/j.coi.2022.102280.
    [2]
    SunZ, HornungV. cGAS-STING signaling[J]. Curr Biol, 2022, 32(13): R730-R734. DOI: 10.1016/j.cub.2022.05.027.
    [3]
    IshikawaH, BarberGN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J]. Nature, 2008, 455(7213): 674-678. DOI: 10.1038/nature07317.
    [4]
    MorereJ, HognonC, MiclotT, et al. How fragile we are: influence of stimulator of interferon genes (STING) variants on pathogen recognition and immune response efficiency[J]. J Chem Inf Model, 2022, 62(12): 3096-3106. DOI: 10.1021/acs.jcim.2c00315.
    [5]
    Messaoud-NacerY, CulerierE, RoseS, et al. STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)[J]. Cell Death Dis, 2022, 13(3): 269. DOI: 10.1038/s41419-022-04664-5.
    [6]
    GuoXF, WuY, JiaQ, et al. PERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in sepsis-associated encephalopathy[J]. CNS Neurosci Ther, 2023, 29(4): 1178-1191. DOI: 10.1111/cns.14095.
    [7]
    LiJY, RenC, WangLX, et al. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis[J]. Cell Death Dis, 2021, 12(9): 834. DOI: 10.1038/s41419-021-04122-8.
    [8]
    DixonSJ, OlzmannJA. The cell biology of ferroptosis[J]. Nat Rev Mol Cell Biol, 2024, 25(6):424-442. DOI: 10.1038/s41580-024-00703-5.
    [9]
    TuoQZ, LiuY, XiangZ, et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion[J]. Signal Transduct Target Ther, 2022, 7(1):59. DOI: 10.1038/s41392-022-00917-z.
    [10]
    ZhangHL, HuBX, LiZL, et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis[J]. Nat Cell Biol, 2022, 24(1):88-98. DOI: 10.1038/s41556-021-00818-3.
    [11]
    ZhouX, ZhaoR, LvMF, et al. ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression[J]. Brain Behav Immun, 2023, 109:331-343. DOI: 10.1016/j.bbi.2023.02.012.
    [12]
    JiaB, LiJ, SongY, et al. ACSL4-mediated ferroptosis and its potential role in central nervous system diseases and injuries[J]. Int J Mol Sci, 2023, 24(12) :10021. DOI: 10.3390/ijms241210021.
    [13]
    HeS, LiR, PengY, et al. ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke[J]. J Cachexia Sarcopenia Muscle, 2022, 13(3):1717-1730. DOI: 10.1002/jcsm.12953.
    [14]
    LanJ, DengZ, WangQ, et al. Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway[J]. Int J Biol Sci, 2024, 20(7):2507-2531. DOI: 10.7150/ijbs.94548.
    [15]
    WangME, ChenJQ, LuY, et al. RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis[J]. J Clin Invest, 2023, 133(10):e166647. DOI: 10.1172/JCI166647.
    [16]
    LuZQ, ZhangC, ZhaoLJ, et al. Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/β-catenin pathway[J/OL]. Burns Trauma, 2024, 12:tkad025[2024-05-18]. https://pubmed.ncbi.nlm.nih.gov/38425412/.DOI: 10.1093/burnst/tkad025.
    [17]
    姚咏明, 张卉, 吴瑶. 靶向树突状细胞的脓毒症免疫调理新策略[J]. 中华烧伤与创面修复杂志, 2023, 39(7): 606-611. DOI: 10.3760/cma.j.cn501225-20230321-00087.
    [18]
    姚咏明, 栾樱译. 严重烧创伤感染及其并发症的免疫新认识[J]. 中华烧伤杂志, 2021, 37(6): 519-523. DOI: 10.3760/cma.j.cn501120-20210118-00025.
    [19]
    贺鹏翼,董宁,吴瑶,等.脓毒症小鼠脾脏树突状细胞焦亡及其对炎症反应和免疫功能的影响[J].解放军医学杂志,2023,48(5):537-544. DOI: 10.11855/j.issn.0577-7402.2023.05.0537.
    [20]
    ZhangQ, WeiJ, LiuZ, et al. STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice[J]. Redox Biol, 2022, 54: 102367. DOI: 10.1016/j.redox.2022.102367.
    [21]
    HuQ, RenH, LiG, et al. STING-mediated intestinal barrier dysfunction contributes to lethal sepsis[J]. EBioMedicine, 2019, 41: 497-508. DOI: 10.1016/j.ebiom.2019.02.055.
    [22]
    CaiY, ChenX, LuT, et al. Activation of STING by SAMHD1 deficiency promotes PANoptosis and enhances efficacy of PD-L1 blockade in diffuse large B-cell lymphoma[J]. Int J Biol Sci, 2023, 19(14): 4627-4643. DOI: 10.7150/ijbs.85236.
    [23]
    XiaoY, ZhaoC, TaiY, et al. STING mediates hepatocyte pyroptosis in liver fibrosis by epigenetically activating the NLRP3 inflammasome[J]. Redox Biol, 2023, 62:102691. DOI: 10.1016/j.redox.2023.102691.
    [24]
    TaniT, MathsyarajaH, CampisiM, et al. TREX1 inactivation unleashes cancer cell STING-interferon signaling and promotes antitumor immunity[J]. Cancer Discov, 2024, 14(5):752-765. DOI: 10.1158/2159-8290.CD-23-0700.
    [25]
    WuX, JiangY, LiR, et al. Ficolin B secreted by alveolar macrophage exosomes exacerbates bleomycin-induced lung injury via ferroptosis through the cGAS-STING signaling pathway[J]. Cell Death Dis, 2023, 14(8): 577. DOI: 10.1038/s41419-023-06104-4.
    [26]
    HuX, ZhangH, ZhangQ, et al. Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis[J]. J Neuroinflammation, 2022, 19(1):242. DOI: 10.1186/s12974-022-02602-y.
    [27]
    ZhaoQX, YanSB, WangF, et al. STING deficiency alleviates ferroptosis through FPN1 stabilization in diabetic kidney disease[J]. Biochem Pharmacol, 2024, 222:116102. DOI: 10.1016/j.bcp.2024.116102.
    [28]
    WuJ, LiuQ, ZhangX, et al. The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages[J]. Cell Death Dis, 2022, 13(7): 653. DOI: 10.1038/s41419-022-05115-x.
    [29]
    GaoL, ZhangJ, YangT, et al. STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease[J]. Mol Ther, 2023, 31(10): 3084-3103. DOI: 10.1016/j.ymthe.2023.07.026.
    [30]
    ChenJ, ChenP, SongY, et al. STING upregulation mediates ferroptosis and inflammatory response in lupus nephritis by upregulating TBK1 and activating NF-κB signal pathway[J]. J Biosci, 2024, 49:9. DOI: 10.1007/s12038-023-00381-z.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(8)  / Tables(3)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (73) PDF downloads(8) Cited by()
    Proportional views
    Related

    Copyright © Chinese Journal of Burns京ICP备07035254号-14

    E-mail：shaoshangzazhi@163.com

    Website：https://zhsszz.xml-journal.net/

    Supported by: Beijing Renhe Information Technology Co. Ltd    

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return