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

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: Boyd Kenkhuis, Michelle van Eekeren, David A Parfitt, Yavuz Ariyurek, Poulomi Banerjee, Josef Priller, Louise van der Weerd, Willeke M C van Roon-Mom
• Journal: Stem cell reports (Stem Cell Reports) Vol. 17 Issue 6 Pg. 1351-1365 (06 14 2022) ISSN: 2213-6711 [Electronic] United States
• PMID: 35523178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Interferon-gamma
• Ferritins
• Iron

Topics

• Amyloid beta-Peptides (metabolism)
• Ferritins (metabolism)
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Inflammation (metabolism)
• Interferon-gamma (metabolism, pharmacology)
• Iron (metabolism)
• Microglia (metabolism)
• Oxidative Stress