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Published on: May 4, 2020
PM2.5 induce neurotoxicity via iron overload and redox imbalance mediated-ferroptosis in HT22 cells
Shuhui Liu1, Aiqing Wang2, Danhong Zhou2
1School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China.
Abstract:
PM2.5 is an important risk factor for the development and progression of cognitive impairment-related diseases. Ferroptosis, a new form of cell death driven by iron overload and lipid peroxidation, is proposed to have significant implications. To verify the possible role of ferroptosis in PM2.5-induced neurotoxicity, we investigated the cytotoxicity, intracellular iron content, iron metabolism-related genes, oxidative stress indices and indicators involving in Nrf2 and ferroptosis signaling pathways. Neurotoxicity biomarkers as well as the ferroptotic cell morphological changes were determined by Western Blot and TEM analysis. Our results revealed that PM2.5 induced cytotoxicity, lipid peroxidation, as indicated by MDA content, and neurotoxicity via Aβ deposition in a dose-related manner. Decreased cell viability and excessive iron accumulation in HT-22 cells can be partially blocked by ferroptosis inhibitors. Interestingly, GPX activity, Nrf2, and its regulated ferroptotic-related proteins (i.e. GPX4 and HO-1) were significantly up-regulated by PM2.5. Moreover, gene expression of DMT1, TfR1, IRP2 and FPN1 involved in iron homeostasis and NCOA4-dependent ferritinophagy were activated after PM2.5 exposure. The results demonstrated that PM2.5 triggered ferritinophagy-dependent ferroptotic cell death due to iron overload and redox imbalance. Activation of Nrf2 signaling pathways may confer a protective mechanism for PM2.5-induced oxidative stress and ferroptosis.
Insights
Air pollution particle PM2.5 triggers ferroptosis, a cell death pathway, contributing to neurotoxicity. Nrf2 pathway activation may offer protection against PM2.5-induced harm.
Area of Science:
- Environmental Health
- Neuroscience
- Cell Biology
Background:
- Particulate Matter (PM2.5) is a significant risk factor for cognitive impairment.
- Ferroptosis, a cell death mode linked to iron overload and lipid peroxidation, is implicated in disease.
- The role of ferroptosis in PM2.5-induced neurotoxicity requires investigation.
Purpose of the Study:
- To investigate the role of ferroptosis in PM2.5-induced neurotoxicity.
- To examine the effects of PM2.5 on cell viability, iron metabolism, oxidative stress, and ferroptosis pathways in neuronal cells.
- To explore the involvement of the Nrf2 signaling pathway.
Main Methods:
- Exposure of HT-22 cells to PM2.5.
- Assessment of cytotoxicity, lipid peroxidation (MDA), intracellular iron, and Aβ deposition.
- Analysis of iron metabolism genes (DMT1, TfR1, IRP2, FPN1) and ferroptosis markers (GPX4, HO-1).
- Western Blot and Transmission Electron Microscopy (TEM) for neurotoxicity biomarkers and ferroptotic changes.
- Evaluation of Nrf2 pathway activation and ferroptosis inhibitors.
Main Results:
- PM2.5 exposure induced dose-dependent cytotoxicity, lipid peroxidation, and neurotoxicity via Aβ deposition.
- PM2.5 caused excessive iron accumulation and decreased cell viability, partially mitigated by ferroptosis inhibitors.
- PM2.5 upregulated Nrf2, GPX activity, GPX4, and HO-1, indicating oxidative stress and ferroptosis pathway activation.
- Gene expression related to iron homeostasis and ferritinophagy was activated.
- PM2.5 triggered ferritinophagy-dependent ferroptosis.
Conclusions:
- PM2.5 exposure induces neurotoxicity and cell death through ferroptosis, driven by iron overload and redox imbalance.
- The Nrf2 signaling pathway is activated in response to PM2.5, potentially offering a protective mechanism against oxidative stress and ferroptosis.
- Ferroptosis is a key mechanism in PM2.5-induced neuronal damage, highlighting potential therapeutic targets.
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