Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG--repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine--2,3--dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron--supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC 50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171--82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD.

Species Differences in Tryptophan Metabolism and Disposition

“…By contrast, the effects of Fe on IDO1 activity appear to be cell- and/or tissue-dependent. Thus, Fe activates IDO1 in brain, and cultured microglia and the purified human recombinant enzyme, 236 but inhibits the IFN-γ induction of the enzyme in Hep-2 cells. 237 Whereas iron deficiency anaemia can exert profound effects on the immune system including cytokine abnormalities, 238 , 239 sequestration of Fe blocks its IDO activation.…”

“… 237 Whereas iron deficiency anaemia can exert profound effects on the immune system including cytokine abnormalities, 238 , 239 sequestration of Fe blocks its IDO activation. 236 Clearly more systematic studies in this area are warranted.…”

New Target for Prevention and Treatment of Neuroinflammation: Microglia Iron Accumulation and Ferroptosis

“…The activation of the kynurenine pathway (KP) for tryptophan degradation promoted the progress of HD. Indoleamine-2,3-dioxygenase (IDO) expressed in microglia was the key enzyme of the KP (Donley et al, 2021). After neonatal HD mice were supplemented with iron, microglia were activated and IDO activity was increased, thus activating KP pathway and promoting the progress of HD (Donley et al, 2021).…”

NAD+ Metabolism, Metabolic Stress, and Infection

“…Heme appears to be a limiting factor for de novo NAD + biosynthesis, as heme titration by apo-myoglobin significantly reduces IDO1 activity ( Nelp et al, 2018 ), which mediates the rate limiting step of de novo metabolism ( Dey et al, 2017 ). IDO1 binding to heme is also influenced by iron, with iron supplementation significantly raising IDO1 activity ( Donley et al, 2019 ). Moreover, the oxidation state of iron is also an important factor in IDO1-heme interaction, with IDO1 showing approximately 10-fold greater affinity for heme in the presence of ferrous (Fe 2+ ) vs. ferric (Fe 3+ ) iron ( Nelp et al, 2018 ).…”