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IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression
Simin Zhou1,2,3, Zhifeng Zhong1,2,3, Pei Huang1,2,3
1Department of High Altitude Operational Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing, China.
Frontiers in Physiology
|November 8, 2021
Summary
Hypobaric hypoxia triggers neuron apoptosis by upregulating phosphorylated signal transducer and activator of transcription 3 (p-STAT3) which downregulates activating transcription factor 6 (ATF6), leading to endoplasmic reticulum stress and cognitive impairment.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Hypobaric hypoxia induces cognitive impairment through hippocampal neuron apoptosis.
- Endoplasmic reticulum (ER) stress, particularly the activating transcription factor 6 (ATF6) pathway, is implicated in this process.
- The precise role of ATF6 in neuron survival and its upstream regulation under hypoxia remains unclear.
Purpose of the Study:
- To investigate the role of signal transducer and activator of transcription 3 (STAT3) phosphorylation in regulating ATF6 and endoplasmic reticulum stress.
- To elucidate the mechanism by which hypobaric hypoxia induces neuron apoptosis.
- To explore the upstream regulation of ATF6 in the context of hypoxia-induced neuroinflammation and apoptosis.
Main Methods:
- Establishment of a hypobaric hypoxia murine model and hypoxia-exposed cell lines (PC12, HT22).
- Measurement of inflammatory cytokines (IL-6, IL-1β, IL-10) using ELISA.
- Assessment of ER stress markers (ATF6, GRP78, CHOP) and p-STAT3 (Tyr705) via Western blot, immunofluorescence, and qRT-PCR.
- Manipulation of STAT3 activity using siRNA and IL-6 treatment.
- Chromatin immunoprecipitation sequencing (ChIP-seq) to determine STAT3 binding to the ATF6 promoter.
Main Results:
- Hypobaric hypoxia increased IL-6 and neuron apoptosis, while decreasing IL-10.
- Expressions of ER stress proteins (ATF6, GRP78, CHOP) and p-STAT3 (Tyr705) were elevated under hypoxia.
- STAT3 silencing promoted ATF6 and inhibited CHOP, whereas STAT3 activation had the opposite effect.
- p-STAT3 (Tyr705) was found to bind to the ATF6 promoter region.
Conclusions:
- Phosphorylation of STAT3 at Tyr705 downregulates ATF6, contributing to hypoxia-induced neuron apoptosis.
- This mechanism links inflammatory responses and endoplasmic reticulum stress to hippocampal neuron apoptosis.
- The findings provide insights into the molecular pathways underlying cognitive impairment in hypobaric hypoxia.
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