Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
Int Immunopharmacol. 2023 Oct;123:110759. doi: 10.1016/j.intimp.2023.110759. Epub 2023 Aug 7.
Neutrophil extracellular traps (NETs) play an important role in sepsis-related acute lung injury (ALI). Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes and miRNA are becoming promising agents for the treatment of ALI. The current study aimed to elucidate the mechanism by BMSCs-derived exosomes carrying miR-127-5p inhibiting to the formation of NETs in sepsis-related ALI. We successfully isolated exosomes from BMSCs and confirmed that miR-127-5p was enriched in the exosomes. ALI mice treated with BMSCs-derived exosomes histologically improved, and the release of NETs and inflammatory factors in lung tissue and peripheral blood of mice also decreased compared with LPS group, while the protective effect of exosomes was attenuated after the knockdown of miR-127-5p. Using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay, we identified CD64 as a direct target of miR-127-5p. Meanwhile, BMSCs-derived exosomes can synergize with anti-CD64 mab in ALI mice to reduce tissue damage, inhibit the release of inflammatory factors and NETs formation. The synergistic effect of exosomes was attenuated when miR-127-5p was down-regulated. These findings suggest that exosomal miR-127-5p derived from BMSCs is a potential therapeutic agent for treatment of sepsis-induced ALI through reducing NETs formation by targeting CD64.
中性粒细胞胞外诱捕网（NETs）在与脓毒症相关的急性肺损伤（ALI）中起着重要作用。骨髓间充质干细胞（BMSCs）衍生的外泌体和 miRNA 成为治疗 ALI 的有前途的药物。本研究旨在阐明 BMSCs 衍生的携带 miR-127-5p 的外泌体抑制脓毒症相关 ALI 中 NETs 形成的机制。我们成功地从 BMSCs 中分离出外泌体，并证实 miR-127-5p 在外泌体中富集。与 LPS 组相比，用 BMSCs 衍生的外泌体治疗的 ALI 小鼠在组织学上得到改善，肺组织和小鼠外周血中 NETs 和炎症因子的释放也减少，而在敲低 miR-127-5p 后，外泌体的保护作用减弱。通过双荧光素酶报告基因检测和 RNA 免疫沉淀（RIP）实验，我们确定 CD64 是 miR-127-5p 的直接靶标。同时，BMSCs 衍生的外泌体可以与抗 CD64 mab 协同作用，减少 ALI 小鼠的组织损伤，抑制炎症因子的释放和 NETs 的形成。当 miR-127-5p 下调时，外泌体的协同作用减弱。这些发现表明，BMSCs 衍生的外泌体 miR-127-5p 通过靶向 CD64 减少 NETs 的形成，是治疗脓毒症诱导的 ALI 的一种潜在治疗药物。
