Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
Mol Ther. 2019 Oct 2;27(10):1758-1771. doi: 10.1016/j.ymthe.2019.07.003. Epub 2019 Jul 15.
Emerging evidence has revealed that excessive activation of macrophages may result in an adverse lung inflammation involved in sepsis-related acute lung injury (ALI). However, it has never been clearly identified whether peripheral circulating serum exosomes participate in the pathogenesis of sepsis-related ALI. Therefore, the purposes of our study were to investigate the effect of serum exosomes on macrophage activation and elucidate a novel mechanism underlying sepsis-related ALI. Here we found that exosomes were abundant in the peripheral blood from ALI mice and selectively loaded microRNAs (miRNAs), such as miR-155. In vivo experiments revealed that intravenous injection of serum exosomes harvested from ALI mice, but not control mice, increased the number of M1 macrophages in the lung, and it caused lung inflammation in naive mice. In vitro, we demonstrated that serum exosomes from ALI mice delivered miR-155 to macrophages, stimulated nuclear factor κB (NF-κB) activation, and induced the production of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. Furthermore, we also showed that serum exosome-derived miR-155 promoted macrophage proliferation and inflammation by targeting SHIP1 and SOCS1, respectively. Collectively, our data suggest the important role of circulating exosomes secreted into peripheral blood as a key mediator of septic lung injury via exosome-shuttling miR-155.
新出现的证据表明，巨噬细胞的过度激活可能导致与脓毒症相关的急性肺损伤 (ALI) 相关的不利肺炎症。然而，外周循环血清外泌体是否参与脓毒症相关 ALI 的发病机制从未被明确识别。因此，我们的研究目的是研究血清外泌体对巨噬细胞激活的影响，并阐明脓毒症相关 ALI 的新机制。在这里，我们发现外泌体在 ALI 小鼠的外周血中丰富，并选择性地装载 microRNAs（miRNAs），如 miR-155。体内实验表明，静脉注射来自 ALI 小鼠而非对照小鼠的血清外泌体增加了肺中 M1 巨噬细胞的数量，并导致了未感染小鼠的肺部炎症。在体外，我们证明了来自 ALI 小鼠的血清外泌体将 miR-155 递送至巨噬细胞，刺激核因子 κB（NF-κB）的激活，并诱导肿瘤坏死因子 α（TNF-α）和白细胞介素（IL）-6 的产生。此外，我们还表明，血清外泌体衍生的 miR-155 通过分别靶向 SHIP1 和 SOCS1 促进巨噬细胞增殖和炎症。总之，我们的数据表明，循环外泌体作为通过外泌体转移 miR-155 介导的脓毒症肺损伤的关键介质，在外周血中分泌到循环中具有重要作用。
