Inflaming the Brain with Iron

Abstract

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood–brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.

Loss of park7 activity has differential effects on expression of iron responsive element (IRE) gene sets in the brain transcriptome in a zebrafish model of Parkinson’s disease

“…The highly significant alteration of expression of the HQ5′IRE gene set in 4-month-old park7 −/− brains is likely due to changes in binding of IRP1 and/ or IRP2 to IREs in the transcripts of these genes. However, since mutation of PARK7 is known to cause oxidative stress [11] and oxidative stress can also affect IRP formation (reviewed in [6]), it is difficult to differentiate between oxidative stress and iron dyshomeostasis as contributing to changes in HQ5′IRE gene transcript abundance. Indeed, since iron is so important for mitochondrial function, iron dyshomeostasis and oxidative stress often co-occur [12].…”

“…IRP1 and IRP2 bind IREs in the mRNAs of genes involved in iron homeostasis to regulate their translation and stability (reviewed in [6]). IRPs are regulated both by cellular ferrous iron status and oxidative stress [6].…”

“…IRP1 and IRP2 bind IREs in the mRNAs of genes involved in iron homeostasis to regulate their translation and stability (reviewed in [6]). IRPs are regulated both by cellular ferrous iron status and oxidative stress [6]. Previously, we defined sets of genes bearing IREs in either the 5′ or 3′UTRs of their transcripts (at lower or higher similarity to an IRE consensus sequence) in humans, mice and zebrafish [7].…”

Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson’s Disease

“…Intracellular iron levels modulate differentiation towards one or the other phenotype [ 110 ]. An iron overload triggers M1 polarization via an ROS-mediated mechanism [ 111 ], increasing TNF and IL1B secretion [ 112 ], and causes M2 macrophages to switch their phenotype to M1 [ 113 ].…”

The Macrophage Iron Signature in Health and Disease

“…In addition, it prevents the infiltration of peripheral MΦ into the brain. Traumatic brain injury, inflammation, or late-stage disease states can lead to a disruption of the BBB, thereby allowing monocyte-derived MΦ to infiltrate, as well as the accumulation of iron, finally leading to ROS production and cellular damage [251,252].…”