4.5 Article

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

Journal

JOURNAL OF NEUROCHEMISTRY
Volume 154, Issue 2, Pages 177-189

Publisher

WILEY
DOI: 10.1111/jnc.14906

Keywords

Alzheimer's disease; divalent metal transporter-1; IMG (immortalized microglia) cells; iron; microglia; neuroinflammation

Funding

  1. NIDDK NIH HHS [R01 DK064750] Funding Source: Medline
  2. NIEHS NIH HHS [T32 ES016645] Funding Source: Medline

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Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta (A beta) senile plaques in patients' brain tissues. Elevated levels of interleukin-1beta (IL-1 beta) have been identified in cerebrospinal fluid of living AD patients and in animal models of AD. Increased expression of IL-1 beta and iron accumulation have been identified in microglial cells that cluster around amyloid plaques in AD mouse models and post-mortem brain tissues of AD patients. The goals of this study were to determine the effects of A beta on the secretion of IL-1 beta by microglial cells and whether iron status influences this pro-inflammatory signaling cue. Immortalized microglial (IMG) cells were incubated with A beta with or without iron. qRT-PCR and western blot analyses showed that A beta induces biosynthesis of IL-1 beta by IMG cells. IMG cells secrete the mature form of IL-1 beta in a caspase 1-dependent manner. Incubation with iron provoked a greater pro-inflammatory response. Inhibition of the iron transporter divalent metal transporter 1 protected IMG cells against A beta-induced inflammation. Potentiation of A beta-elicited IL-1 beta induction by iron was also antagonized by ROS inhibitors, supporting the model that divalent metal transporter 1-mediated iron loading and subsequent increase in ROS contribute to the inflammatory effects of A beta in microglia. Immunoblotting and immunofluorescence microscopy indicate that iron enhances A beta activation of NF-kappa B signaling to promote IL-1 beta synthesis. These results support the hypothesis that A beta stimulates IL-1 beta expression by activating NF-kappa B signaling in microglia cells. Most importantly, iron appears to exacerbate the pro-inflammatory effects of A beta to increase IL-1 beta levels.

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