Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
J Gastroenterol Hepatol. 2022 Dec;37(12):2243-2254. doi: 10.1111/jgh.15987. Epub 2022 Sep 25.
Programmed death-ligand 1 (PD-L1) was involved in regulating Th17/Treg cell balance in ulcerative colitis (UC). Extracellular vesicles (EVs) from genetically modified bone marrow mesenchymal stem cells (BMSCs) can serve as a stable delivery system to overexpress PD-L1. The study was designed to evaluate the therapeutic mechanism of BMSC-EVs overexpressing PD-L1 (PD-L1-EVs) on ulcerative colitis.
Experimental model of UC was established in rats by drinking 5% dextran sulfate sodium (DSS). Apoptosis-related proteins, inflammatory response-related factors and oxidative stress related mediators were detected. Westernblot was used to detecte key proteins in the PI3K/AKT signaling pathway and its downstream effectors. The CD4 Foxp3 Treg cells and CD4 IL-17A Th17 cells in spleen and mesenteric lymph nodes (MLNs) was detected by flow cytometry.
PD-L1-EVs significantly alleviated the manifestations and pathological damage of UC rats by inhibiting the expression of IFN-γ, IL-1β, IL-8, IL-6, IL-2, BAX, NF-κB, TNF-α, MPO, and MDA, and up-regulating the expression of IL-4, BCL-2, SOD, and GSH. Furthermore, the proportions of Th17 cells were decreased and that of Treg cells were upregulated by PD-L1-EVs treatment. PTEN inhibitors (bpv) partially abolished the inhibitory effect of PD-L1-EVs on PI3K-AKT signaling and impaired the therapeutic efficacy of PD-L1-EVs.
PD-L1-EVs mitigated colonal inflammation, apoptosis and oxidative stress through blocking the activation of PI3K/Akt/mTOR pathway and regulating the balance of Th17/Treg cells.
程序性死亡配体 1（PD-L1）参与调节溃疡性结肠炎（UC）中的 Th17/Treg 细胞平衡。来自基因修饰的骨髓间充质干细胞（BMSC）的细胞外囊泡（EVs）可作为过表达 PD-L1 的稳定递送系统。本研究旨在评估过表达 PD-L1 的 BMSC-EVs（PD-L1-EVs）对溃疡性结肠炎的治疗机制。
通过饮用 5%葡聚糖硫酸钠（DSS）建立 UC 大鼠实验模型。检测凋亡相关蛋白、炎症反应相关因子和氧化应激相关介质。Western blot 检测 PI3K/AKT 信号通路及其下游效应物中的关键蛋白。通过流式细胞术检测脾脏和肠系膜淋巴结（MLNs）中的 CD4 Foxp3 Treg 细胞和 CD4 IL-17A Th17 细胞。
PD-L1-EVs 通过抑制 IFN-γ、IL-1β、IL-8、IL-6、IL-2、BAX、NF-κB、TNF-α、MPO 和 MDA 的表达，上调 IL-4、BCL-2、SOD 和 GSH 的表达，显著缓解 UC 大鼠的表现和病理损伤。此外，PD-L1-EVs 处理降低了 Th17 细胞的比例，上调了 Treg 细胞的比例。PTEN 抑制剂（bpv）部分消除了 PD-L1-EVs 对 PI3K-AKT 信号的抑制作用，并损害了 PD-L1-EVs 的治疗效果。
PD-L1-EVs 通过阻断 PI3K/Akt/mTOR 通路的激活和调节 Th17/Treg 细胞平衡，减轻结肠炎症、凋亡和氧化应激。
