Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
CNS Neurosci Ther. 2024 Mar;30(3):e14454. doi: 10.1111/cns.14454. Epub 2023 Sep 12.
We investigated whether human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes bear therapeutic potential against lipopolysaccharide (LPS)-induced neuroinflammation.
Exosomes were isolated from hUC-MSC supernatant by ultra-high-speed centrifugation and characterized by transmission electron microscopy and western blotting. Inflammatory responses were induced by LPS in BV-2 cells, primary microglial cultures, and C57BL/6J mice. H O was also used to induce inflammation and oxidative stress in BV-2 cells. The effects of hUC-MSC-derived exosomes on inflammatory cytokine expression, oxidative stress, and microglia polarization were studied by immunofluorescence and western blotting.
Treatment with hUC-MSC-derived exosomes significantly decreased the LPS- or H O -induced oxidative stress and expression of pro-inflammatory cytokines (IL-6 and TNF-α) in vitro, while promoting an anti-inflammatory (classical M2) phenotype in an LPS-treated mouse model. Mechanistically, the exosomes increased the NRF2 levels and inhibited the LPS-induced NF-κB p65 phosphorylation and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and NF-κB inhibitor BAY 11-7082 also inhibited the LPS-induced NLRP3 inflammasome activation and switched to the classical M2 phenotype. Treatment with the NRF2 inhibitor ML385 abolished the anti-inflammatory and anti-oxidative effects of the exosomes.
hUC-MSC-derived exosomes ameliorated LPS/H O -induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF-κB/NLRP3 signaling pathway.
我们研究了人脐带间充质干细胞（hUC-MSC）衍生的外泌体是否具有针对脂多糖（LPS）诱导的神经炎症的治疗潜力。
通过超速离心从 hUC-MSC 上清液中分离出外泌体，并通过透射电子显微镜和 Western blot 进行表征。在 BV-2 细胞、原代小胶质细胞培养物和 C57BL/6J 小鼠中用 LPS 诱导炎症反应。还用 H2O2 诱导 BV-2 细胞的炎症和氧化应激。通过免疫荧光和 Western blot 研究 hUC-MSC 衍生的外泌体对炎症细胞因子表达、氧化应激和小胶质细胞极化的影响。
hUC-MSC 衍生的外泌体处理可显著降低 LPS 或 H2O2 诱导的体外氧化应激和促炎细胞因子（IL-6 和 TNF-α）的表达，同时在 LPS 处理的小鼠模型中促进抗炎（经典 M2）表型。在机制上，外泌体增加了 NRF2 水平，并抑制了 LPS 诱导的 NF-κB p65 磷酸化和 NLRP3 炎性小体激活。相比之下，活性氧清除剂 NAC 和 NF-κB 抑制剂 BAY 11-7082 也抑制了 LPS 诱导的 NLRP3 炎性小体激活，并转变为经典 M2 表型。用 NRF2 抑制剂 ML385 处理可消除外泌体的抗炎和抗氧化作用。
hUC-MSC 衍生的外泌体通过抑制小胶质细胞 NRF2/NF-κB/NLRP3 信号通路改善了 LPS/H2O2 诱导的神经炎症和氧化应激。
