Department of Critical Care Medicine, Beijing Jishuitan Hospital, Beijing 100035, China.
Department of Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.
Mediators Inflamm. 2022 Jul 23;2022:6077570. doi: 10.1155/2022/6077570. eCollection 2022.
When sepsis attacks the body, the excessive reactive oxygen species (ROS) production can result to endoplasmic reticulum stress (ERS) and eventually cause lymphocyte apoptosis. The mammalian target of rapamycin (mTOR) is essential for regulating lymphocyte apoptosis; we hypothesized that it mediates CD4 T cell apoptosis during ROS-related ERS.
We, respectively, used ROS and ERS blockers to intervene septic mice and then detected ERS protein expression levels to verify the relationship between them. Additionally, we constructed T cell-specific mTOR and TSC1 gene knockout mice to determine the role of mTOR in ROS-mediated, ERS-induced CD4 T cell apoptosis.
Blocking ROS significantly suppressed the CD4 T cell apoptosis associated with the reduction in ERS, as revealed by lower levels of GRP78 and CHOP. ERS rapidly induced mTOR activation, leading to the induction of CD4 T cell apoptosis. However, mTOR knockout mice displayed reduced expression of apoptotic proteins and less ER vesiculation and expansion than what was observed in the wild-type sepsis controls.
By working to alleviate ROS-mediated, ERS-induced CD4 T cell apoptosis, the mTOR pathway is vital for CD4 T cell survival in sepsis mouse model.
当败血症攻击身体时，过多的活性氧（ROS）的产生会导致内质网应激（ERS），并最终导致淋巴细胞凋亡。雷帕霉素靶蛋白（mTOR）对于调节淋巴细胞凋亡是必不可少的；我们假设它在 ROS 相关的 ERS 期间介导 CD4 T 细胞凋亡。
我们分别使用 ROS 和 ERS 阻滞剂来干预败血症小鼠，然后检测 ERS 蛋白表达水平，以验证它们之间的关系。此外，我们构建了 T 细胞特异性 mTOR 和 TSC1 基因敲除小鼠，以确定 mTOR 在 ROS 介导的、ERS 诱导的 CD4 T 细胞凋亡中的作用。
阻断 ROS 显著抑制了与 ERS 减少相关的 CD4 T 细胞凋亡，这表现为 GRP78 和 CHOP 的水平降低。ERS 迅速诱导 mTOR 激活，导致 CD4 T 细胞凋亡。然而，与野生型败血症对照相比，mTOR 敲除小鼠的凋亡蛋白表达减少，内质网泡形成和扩张减少。
通过减轻 ROS 介导的、ERS 诱导的 CD4 T 细胞凋亡，mTOR 通路对于败血症小鼠模型中 CD4 T 细胞的存活至关重要。
