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Iron accumulation induces oxidative stress, while depressing inflammatory polarization in human iPSC-derived
Boyd Kenkhuis1, Michelle van Eekeren2, David A Parfitt2
1Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK.
Abstract:
Iron accumulation in microglia has been observed in Alzheimer's disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms, including neuroinflammation. To study this interaction, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with iron, in combination with inflammatory stimuli such as interferon gamma (IFN-γ) and amyloid β. Both IFN-γ and iron treatment increased labile iron levels, but only iron treatment led to a consistent increase of ferritin levels, reflecting long-term iron storage. Therefore, in iPSC-MG, ferritin appeared to be regulated by iron revels rather than inflammation. Further investigation showed that while IFN-γ induced pro-inflammatory activation, iron treatment dampened both classic pro- and anti-inflammatory activation on a transcriptomic level. Notably, iron-loaded microglia showed strong upregulation of cellular stress response pathways, the NRF2 pathway, and other oxidative stress pathways. Functionally, iPSC-MG exhibited altered phagocytosis and impaired mitochondrial metabolism following iron treatment. Collectively, these data suggest that in MG, in contrast to current hypotheses, iron treatment does not result in pro-inflammatory activation, but rather dampens it and induces oxidative stress.
Insights
Iron accumulation in microglia, observed in neurodegenerative diseases, does not promote inflammation. Instead, iron overload in microglia dampens inflammatory responses and induces oxidative stress, impacting cellular functions.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Iron accumulation in microglia is a hallmark of neurodegenerative diseases like Alzheimer's.
- This iron buildup is hypothesized to drive neuroinflammation and disease progression.
Purpose of the Study:
- To investigate the effects of iron loading on human induced pluripotent stem cell-derived microglia (iPSC-MG).
- To determine if iron exacerbates or modulates inflammatory responses in microglia.
Main Methods:
- Treatment of iPSC-MG with iron, interferon gamma (IFN-γ), and amyloid-beta.
- Analysis of labile iron, ferritin levels, and transcriptomic changes.
- Assessment of cellular stress, NRF2 pathway activation, phagocytosis, and mitochondrial metabolism.
Main Results:
- Iron treatment increased ferritin levels, indicating long-term storage, while IFN-γ did not.
- Iron dampened pro- and anti-inflammatory transcriptomic activation, contrasting with IFN-γ's pro-inflammatory effect.
- Iron-loaded microglia showed increased cellular stress, NRF2 pathway activation, impaired phagocytosis, and altered mitochondrial metabolism.
Conclusions:
- Contrary to hypotheses, iron does not induce pro-inflammatory activation in microglia.
- Iron loading in microglia primarily induces cellular stress and oxidative pathways, while dampening inflammation.
- These findings suggest a complex role for iron in neurodegeneration beyond simple inflammation induction.
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