Inflammation-induced iron transport and metabolism by brain microglia

Area of Science:

• Neuroimmunology
• Cellular Metabolism
• Metal Ion Homeostasis

Background:

• Microglia are central nervous system immune cells involved in brain inflammation.
• The modulation of iron transport and metabolism by microglia in response to inflammatory cues remains poorly understood.
• Iron is essential for brain function, and its dysregulation is linked to neuroinflammation.

Purpose of the Study:

• To investigate how microglia, specifically immortalized microglial (IMG) cells, transport and metabolize iron in response to pro- and anti-inflammatory stimuli.
• To characterize the uptake of transferrin (Tf)-bound iron (TBI) and non-Tf-bound iron (NTBI) by microglia.
• To determine the impact of inflammatory polarization on microglial iron metabolism and cellular energetics.

Main Methods:

• Characterization of TBI and NTBI uptake in IMG cells stimulated with lipopolysaccharide (LPS), β-amyloid (Aβ), or interleukin 4 (IL-4).
• Analysis of transferrin receptor (TfR), divalent metal transporter-1 (DMT1), and ferritin expression levels.
• Assessment of metabolic changes, including glycolysis and oxidative respiration, and extracellular acidification rate.
• Confirmation of expression changes in primary adult mouse microglia.

Main Results:

• IMG cells preferentially uptake NTBI upon stimulation with proinflammatory LPS or Aβ.
• IL-4, an anti-inflammatory cytokine, promoted TBI uptake and increased TfR levels.
• LPS or Aβ stimulation led to increased DMT1 and ferritin levels, alongside enhanced glycolysis and reduced oxidative respiration.
• LPS increased heme oxygenase-1 (HO1) expression, contributing to the labile free-iron pool and cellular iron sequestration.

Conclusions:

• Microglia exhibit distinct iron acquisition strategies based on their polarization state, favoring NTBI under proinflammatory conditions.
• Proinflammatory stimuli enhance NTBI uptake and alter microglial metabolism, promoting glycolysis and iron sequestration.
• These findings reveal a dynamic interplay between microglial inflammatory status, iron metabolism, and cellular energetics, with implications for neuroinflammatory diseases.