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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
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mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice

Guangxu Bai1, Hao Wang2, Na Cui3,4

  • 1Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100730, China.

Apoptosis : an International Journal on Programmed Cell Death
|June 27, 2022
PubMed

Insights

Mammalian target of rapamycin (mTOR) regulates endoplasmic reticulum stress (ERS)-induced T cell apoptosis in sepsis. The mTOR-Akt-IRE1α-JNK pathway is key to this process, offering potential therapeutic targets for sepsis immune imbalance.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Medicine

Background:

  • Endoplasmic reticulum stress (ERS) contributes to apoptosis in various diseases, but its upstream regulators remain unclear.
  • The protein kinase mammalian target of rapamycin (mTOR) is a critical regulator of apoptosis.
  • Sepsis involves host immune imbalance, partly due to T cell apoptosis.

Purpose of the Study:

  • To investigate the role of mTOR in sepsis-induced T cell apoptosis.
  • To elucidate the upstream signaling pathways and molecular mechanisms linking mTOR, ERS, and T cell apoptosis in sepsis.
  • To explore the mTOR-Akt-IRE1-JNK pathway's involvement in septic T cell apoptosis.

Main Methods:

  • Utilized a cecal ligation and puncture (CLP) sepsis model in T cell-specific knockout mTOR and TSC1 mice.
  • Administered specific inhibitors of PI3K-Akt and IRE1-JNK pathways to mice before/after CLP.
  • Analyzed protein expression within the mTOR-ERS signaling pathway and apoptosis-related proteins/genes.

Main Results:

  • mTOR was found to modulate septic T cell apoptosis via the Akt-IRE1-JNK pathway.
  • mTOR negatively regulated the Akt-IRE1-JNK-Caspase 3 signaling cascade.
  • ERS-induced CD4+ T cell apoptosis in septic mice was mediated by mTOR.

Conclusions:

  • The mTOR-Akt-IRE1α-JNK signaling pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in sepsis.
  • This pathway represents a potential therapeutic target for managing immune dysregulation in sepsis.
  • Understanding mTOR's role in ERS-mediated apoptosis is crucial for sepsis treatment strategies.
Keywords:
ApoptosisCLPEndoplasmic reticulum stressIRE1–JNKMammalian target of rapamycin

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