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

Israel C Nnah, Chih-Hao Lee, Marianne Wessling-Resnick

Journal of neurochemistry 2020 Jul

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Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta (Aβ) senile plaques in patients' brain tissues. Elevated levels of interleukin-1beta (IL-1β) have been identified in cerebrospinal fluid of living AD patients and in animal models of AD. Increased expression of IL-1β 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 Aβ on the secretion of IL-1β by microglial cells and whether iron status influences this pro-inflammatory signaling cue. Immortalized microglial (IMG) cells were incubated with Aβ with or without iron. qRT-PCR and western blot analyses showed that Aβ induces biosynthesis of IL-1β by IMG cells. IMG cells secrete the mature form of IL-1β 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 Aβ-induced inflammation. Potentiation of Aβ-elicited IL-1β 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 Aβ in microglia. Immunoblotting and immunofluorescence microscopy indicate that iron enhances Aβ activation of NF-κB signaling to promote IL-1β synthesis. These results support the hypothesis that Aβ stimulates IL-1β expression by activating NF-κB signaling in microglia cells. Most importantly, iron appears to exacerbate the pro-inflammatory effects of Aβ to increase IL-1β levels. © 2019 International Society for Neurochemistry.

Citation

Israel C Nnah, Chih-Hao Lee, Marianne Wessling-Resnick. Iron potentiates microglial interleukin-1β secretion induced by amyloid-β. Journal of neurochemistry. 2020 Jul;154(2):177-189