Iron potentiates microglial interleukin-1β secretion induced by amyloid-β

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Alzheimer's disease (AD) is linked to amyloid-beta (Aβ) plaques and elevated interleukin-1beta (IL-1β).
• Microglia, brain immune cells, show increased IL-1β expression and iron accumulation around Aβ plaques in AD.
• The interplay between Aβ, iron, and microglial pro-inflammatory responses in AD remains incompletely understood.

Purpose of the Study:

• To investigate the effect of Aβ on IL-1β secretion by microglial cells.
• To determine if iron status modulates Aβ-induced microglial inflammation.
• To elucidate the molecular mechanisms underlying Aβ and iron-mediated inflammatory signaling in microglia.

Main Methods:

• Immortalized microglial (IMG) cells were treated with Aβ and/or iron.
• Gene expression and protein levels of IL-1β were analyzed using qRT-PCR and western blot.
• Caspase-1 activity, reactive oxygen species (ROS) production, and NF-κB signaling activation were assessed.
• The role of the iron transporter divalent metal transporter 1 (DMT1) was investigated.

Main Results:

• Aβ significantly induced IL-1β biosynthesis and secretion in IMG cells in a caspase-1-dependent manner.
• Iron co-incubation potentiated Aβ-induced IL-1β production, increasing pro-inflammatory signaling.
• Inhibition of DMT1 and ROS scavengers attenuated Aβ-induced inflammation, indicating their crucial roles.
• Iron enhanced Aβ-mediated activation of NF-κB signaling pathways.

Conclusions:

• Aβ stimulates IL-1β production in microglia via NF-κB signaling.
• Iron exacerbates Aβ-induced microglial inflammation, partly through DMT1-mediated iron uptake and increased ROS.
• These findings highlight the critical role of iron in modulating neuroinflammation in Alzheimer's disease.