Iron accumulation induces oxidative stress, while depressing inflammatory polarization in human iPSC-derived microglia

Stem Cell Reports, vol. 17, pp. 1351–1365

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.

Authors 8

1. Boyd Kenkhuis corresponding Aachen Department of Human Genetics

   Leiden University Medical Center · UK Dementia Research Institute · University of Edinburgh

   Affiliation as printed

   Department 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. Electronic address: b.kenkhuis@lumc.nl

   Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands

   UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK

2. Michelle van Eekeren Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands

3. David A. Parfitt Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands

4. Yavuz Ariyürek Aachen Leiden Genome Technology Center

   Leiden University Medical Center

   Affiliation as printed

   Leiden Genome Technology Center, Leiden University Medical Center, Leiden, the Netherlands

5. Poulomi Banerjee

   UK Dementia Research Institute · University of Edinburgh

   Affiliation as printed

   Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK

   Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

   UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK

6. Josef Priller

   UK Dementia Research Institute · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Technical University of Munich · Charité - Universitätsmedizin Berlin · University of Edinburgh

   Affiliation as printed

   Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK; Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany; Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité, Universitätsmedizin Berlin, BIH and DZNE, Berlin, Germany

   Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

   Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany

   Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité, Universitätsmedizin Berlin, BIH and DZNE, Berlin, Germany

   UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK

7. Louise van der Weerd Aachen Department of Human Genetics Department of Radiology, Leiden University Medical Center

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands

   Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

8. Willeke van Roon‐Mom Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600, 2300RC Leiden, the Netherlands