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Published on: January 22, 2019
mTOR Modulates the Endoplasmic Reticulum Stress-Induced CD4+ T Cell Apoptosis Mediated by ROS in Septic
Hao Wang1, Jianwei Chen2, Guangxu Bai2
1Department of Critical Care Medicine, Beijing Jishuitan Hospital, Beijing 100035, China.
Introduction:
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.
Method:
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.
Results:
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.
Conclusion:
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.
Insights
Sepsis triggers reactive oxygen species (ROS) and endoplasmic reticulum stress (ERS), leading to CD4+ T cell death. The mammalian target of rapamycin (mTOR) pathway is crucial for this apoptosis, making it a potential therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Sepsis induces excessive reactive oxygen species (ROS) production, causing endoplasmic reticulum stress (ERS).
- ERS can lead to lymphocyte apoptosis, a process critical in immune response regulation.
- The mammalian target of rapamycin (mTOR) pathway plays a key role in regulating lymphocyte apoptosis.
Purpose of the Study:
- To investigate the role of the mammalian target of rapamycin (mTOR) pathway in CD4+ T cell apoptosis during ROS-related endoplasmic reticulum stress (ERS) in sepsis.
- To determine if blocking ROS or ERS affects CD4+ T cell apoptosis.
- To elucidate the mechanism by which mTOR mediates CD4+ T cell apoptosis in a sepsis mouse model.
Main Methods:
- Intervention with ROS and ERS blockers in septic mice.
- Detection of ERS protein expression levels (GRP78 and CHOP).
- Construction of T cell-specific mTOR and TSC1 gene knockout mice to assess mTOR's role in apoptosis.
Main Results:
- Blocking ROS significantly reduced CD4+ T cell apoptosis and ERS.
- Endoplasmic reticulum stress (ERS) rapidly activated mTOR, inducing CD4+ T cell apoptosis.
- mTOR knockout mice exhibited reduced apoptotic protein expression and less ER damage compared to wild-type controls.
Conclusions:
- The mTOR pathway is vital for CD4+ T cell survival during sepsis.
- Alleviating ROS-mediated, ERS-induced CD4+ T cell apoptosis involves the mTOR pathway.
- Targeting the mTOR pathway could be a therapeutic strategy for sepsis.
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