Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Mol Immunol. 2024 Jan;165:42-54. doi: 10.1016/j.molimm.2023.12.005. Epub 2023 Dec 27.
Cells can produce stress granules (SGs) to protect itself from damage under stress. The cGAS-STING pathway is one of the important pattern recognition pathways in the natural immune system. This study was investigated whether human mesenchymal stem cells (hMSCs) could protect the liver by inducing M2 macrophages to produce SGs during acute drug induced liver injury (DILI) induced by acetaminophen (APAP).
After intragastric administration of APAP in vivo to induce DILI mice model, hMSCs were injected into the tail vein. The co-culture system of hMSCs and M2 macrophages was established in vitro. It was further use SGs inhibitor anisomicin to intervene M2 macrophages. The liver histopathology, liver function, reactive oxygen species (ROS) level, apoptosis pathway, endoplasmic reticulum stress (ERS) level, SGs markers (G3BP1/TIA-1), cGAS-STING pathway, TNF-α, IL-6, IL-1β mRNA levels in liver tissue and M2 macrophages were observed.
In vivo experiments, it showed that hMSCs could alleviate liver injury, inhibite the level of ROS, apoptosis and ERS, protect liver function in DILI mice. The mount of M2 was increased in the liver. hMSCs could also induce the production of SGs, inhibit the cGAS-STING pathway and reduce TNF-α, IL-6, IL-1β mRNA expression. The results in vitro showed that hMSCs could induce the production of SGs in macrophages, inhibit the cGAS-STING pathway, promote the secretion of IL-4 and IL-13, and reduce TNF-α, IL-6, IL-1β mRNA level in cells. In the process of IL-4 inducing M2 macrophage activation, anisomycin could inhibit the production of SGs, activate the cGAS-STING pathway, and promote the inflammatory factor TNF-α, IL-6, IL-1β mRNA expression in cells.
HMSCs had a protective effect on acute DILI in mice induced by APAP. Its mechanism might involve in activating M2 type macrophages, promoting the production of SGs, inhibiting the cGAS-STING pathway, and reducing the expression of pro-inflammatory factors in macrophages, to reduce hepatocytes damage.
细胞可以产生应激颗粒 (SGs) 来保护自身免受应激损伤。cGAS-STING 途径是天然免疫系统中重要的模式识别途径之一。本研究探讨了人骨髓间充质干细胞 (hMSCs) 是否可以通过在乙酰氨基酚 (APAP) 诱导的急性药物性肝损伤 (DILI) 期间诱导 M2 巨噬细胞产生 SGs 来保护肝脏。
体内给予 APAP 灌胃诱导 DILI 小鼠模型后，尾静脉注射 hMSCs。体外建立 hMSCs 与 M2 巨噬细胞共培养体系，进一步用 SGs 抑制剂放线菌酮干预 M2 巨噬细胞。观察肝组织病理学、肝功能、活性氧 (ROS) 水平、凋亡通路、内质网应激 (ERS) 水平、SGs 标志物 (G3BP1/TIA-1)、cGAS-STING 通路、TNF-α、IL-6、IL-1β 在肝组织和 M2 巨噬细胞中的 mRNA 水平。
体内实验表明，hMSCs 可减轻 DILI 小鼠肝损伤，抑制 ROS、凋亡和 ERS 水平，保护肝功能。肝脏中 M2 数量增加。hMSCs 还可诱导 SGs 产生，抑制 cGAS-STING 通路，降低 TNF-α、IL-6、IL-1β mRNA 表达。体外实验结果表明，hMSCs 可诱导巨噬细胞产生 SGs，抑制 cGAS-STING 通路，促进 IL-4、IL-13 的分泌，降低细胞内 TNF-α、IL-6、IL-1β mRNA 水平。在 IL-4 诱导 M2 巨噬细胞活化过程中，放线菌酮可抑制 SGs 产生，激活 cGAS-STING 通路，促进细胞内炎症因子 TNF-α、IL-6、IL-1β mRNA 表达。
hMSCs 对 APAP 诱导的急性 DILI 小鼠具有保护作用。其机制可能涉及激活 M2 型巨噬细胞，促进 SGs 的产生，抑制 cGAS-STING 通路，降低巨噬细胞中促炎因子的表达，从而减轻肝细胞损伤。
