骨髓间充质干细胞衍生的外泌体通过抑制巨噬细胞的铁下垂减轻败血症诱导的肺损伤

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-13 DOI:10.1016/j.intimp.2025.114789

Huimin Deng , Wenyu Zhou , Juan Wei , Tian Jin , Yuanli Chen , Lina Zhu , Hao Yang , Xin Lv

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引用次数: 0

摘要

目的：探讨骨髓间充质干细胞衍生外泌体（BMSCs-exo）是否能通过抑制巨噬细胞铁凋亡来减轻脓毒症所致肺损伤及其相关机制。方法：首先用脂多糖（LPS）刺激RAW264.7细胞，观察巨噬细胞是否发生铁下垂。用外泌体抑制剂GW4869预处理骨髓间充质干细胞后，观察其肺保护作用以确定其是否被消除。此外，我们还提取了BMSCs-exo，以明确其是否能发挥与BMSCs类似的作用。最后，通过测序和其他相关技术确定了产生作用的关键分子。结果：LPS刺激后，RAW264.7细胞中GPX4表达显著降低，PTGS2表达显著升高。细胞内GSH含量降低，MDA含量升高。BMSCs-exo逆转了GPX4的减少和PTGS2的增加，GSH的增加和MDA的降低。测序结果显示，与BMSCs-exo共培养后，巨噬细胞中的lncRNA SNHG12显著上调。通过siRNA在骨髓间充质干细胞中敲低lncRNA SNHG12，体内和体外对巨噬细胞铁凋亡的抑制作用均显著降低。结论：BMSCs-exo可通过lncRNA SNHG12抑制巨噬细胞铁沉，从而减轻败血症所致肺损伤，提高生存率。

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Bone marrow mesenchymal stem cell-derived exosomes alleviating sepsis-induced lung injury by inhibiting ferroptosis of macrophages

Objective: To investigate whether bone marrow mesenchymal stem cells derived exosomes (BMSCs-exo) can alleviate sepsis-induced lung injury and its related mechanism by inhibiting ferroptosis of macrophages.

Methods: RAW264.7 cells were first stimulated with lipopolysaccharide (LPS) to observe whether macrophage ferroptosis occurred. After pre-treating BMSCs with the exosome inhibitor GW4869, the lung-protective effect was observed to determine if it was eliminated. Furthermore, BMSCs-exo was extracted to clarify if it could exert effects like BMSCs. Finally, key molecules responsible for the effects were identified through sequencing and other related techniques.

Results: Following stimulation with LPS, the expression of GPX4 in RAW264.7 cells decreased significantly, while the expression of PTGS2 increased significantly. The intracellular GSH content decreased, while MDA content increased. BMSCs-exo reversed the decrease in GPX4 and increase in PTGS2, increased GSH and decreased MDA. Sequencing revealed that lncRNA SNHG12 in macrophages was significantly upregulated after co-culture with BMSCs-exo. Knockdown of lncRNA SNHG12 in BMSCs via siRNA resulted in a significant decrease in the inhibitory effect on macrophage ferroptosis both in vivo and in vitro.

Conclusion: BMSCs-exo can inhibit macrophage ferroptosis through lncRNA SNHG12, thereby alleviating the sepsis-induced lung injury and improving the survival rate.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.