Department of Transplant Surgery, The Third Xiangya Hospital, Central South University, 410013, Changsha, China.
Department of Pathology, The Third Xiangya Hospital, Central South University, 410013, Changsha, China.
Commun Biol. 2024 May 11;7(1):562. doi: 10.1038/s42003-024-06236-z.
MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1. MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1β, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE.
间充质干细胞（MSCs）衍生的外泌体（MSCs-exo）中的 miRNAs 在脓毒症治疗中发挥重要作用。我们探索了 MSCs-exo 影响脓毒症相关脑病（SAE）认知障碍的机制。在这里，我们表明 miR-140-3p 靶向 Hmgb1。MSCs-exo 加 miR-140-3p 模拟物（Exo）和抗生素亚胺培南/西司他丁（ABX）可提高盲肠结扎和穿刺（CLP）小鼠的存活率、体重和认知障碍。Exo 和 ABX 抑制高迁移率族蛋白 B1（HMGB1）、IBA-1、白细胞介素（IL）-1β、IL-6、iNOS、TNF-α、p65/p-p65、NLRP3、Caspase 1 和 GSDMD-N 水平。此外，Exo 增加了 CLP 小鼠海马体中 S-乳酰谷胱甘肽的水平。我们的数据进一步表明，Exo 和 S-乳酰谷胱甘肽增加了 LPS 诱导的 HMC3 细胞中的 GSH 水平，并降低了 LD 和 GLO2 水平，抑制了炎症反应和细胞焦亡。这些发现表明，MSCs-exo 介导的 miR-140-3p 的递送通过 HMGB1 和 S-乳酰谷胱甘肽代谢改善了 SAE 小鼠的认知障碍，为 SAE 的临床治疗提供了潜在的治疗靶点。
