Astrocytic expression of ZIP14 (SLC39A14) is part of the inflammatory reaction in chronic neurodegeneration with iron overload

Abstract

Neurodegeneration is associated with inflammation and mismanaged iron homeostasis, leading to increased concentration of non‐transferrin‐bound iron (NTBI) in the brain. NTBI can be taken up by cells expressing Zrt‐, Irt‐like protein‐14 (ZIP14), which is regulated by iron overload and pro‐inflammatory cytokines, for example, interleukin‐1β (IL‐1β) and IL‐6. Here, we focus on the astrocytic involvement and regulation of ZIP14 in an experimental model of chronic neurodegeneration with inflammation and iron overload. Rats were unilaterally injected with ibotenic acid in striatum resulting in excitotoxicity‐induced neuronal loss in substantia nigra pars reticulata (SNpr). ZIP14 expression was measured in SNpr using immunohistochemistry, western blotting, and RT‐qPCR. Cultures of primary astrocytes were examined for Zip14 mRNA expression after stimulation with ferric ammonium citrate (FAC), IL‐6, or IL‐1β. To study the involvement of ZIP14 in astrocytic iron uptake, uptake of 59Fe was investigated after treatment with IL‐1β and siRNA‐mediated ZIP14 knockdown. In the lesioned SNpr, reactive astrocytes, but not microglia, revealed increased ZIP14 expression with a main confinement to cell bodies and cellular processes. In astrocyte cultures, FAC and IL‐1β stimulation increased Zip14 expression and IL‐1β stimulation increased uptake of 59Fe. Increased 59Fe uptake was also observed after siRNA‐mediated ZIP14 knockdown suggesting that lowering of ZIP14 impaired the balance between astrocytic uptake and export of iron. We conclude that astrocytes increase ZIP14 expression in response to inflammation and iron exposure and that ZIP14 seems pertinent for iron uptake in astrocytes and plays a role for a balanced astrocytic iron homeostasis.

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

“…Microglial cell expression of Vegfa in response to IL-6 may therefore induce both microglial cell proliferation and contribute to pathological angiogenesis observed in the brain of GFAP-IL6 mice [ 8 ]. Aberrant deposition of iron is a prominent feature of neurodegenerative diseases [ 124 , 125 ] and progressively accumulates in the cerebellum of GFAP-IL6 mice, likely as a result of chronic leakage of the blood–brain barrier [ 117 ]. Increased microglial cell expression of IL-6-skewed genes associated with iron ion uptake and transport, such as Slc39a14 and transferrin ( Trf ) [ 126 ], may therefore impart these cells with the ability to sense and take up iron in the brain of GFAP-IL6 mice.…”

Remodeling of the brain angioarchitecture in experimental chronic neurodegeneration

“…At eight weeks, the Wistar rats were stereotactically injected with ibotenic acid (Sigma-Aldrich) into the striatum (Fig. 1A), following the same procedure as previously described [32,33]. In short, 8 weeks old male Wistar rats (Janvier Labs, France) were anesthetized with subcutaneous injection of 0.3 ml/100g body weight hypnorm-dormicum (0.315 mg/ml fentanyl and 10 mg/ml fluanisone mixed with 5 mg/ml midazolam in sterile water, 1:1:2).…”

“…This imbalance between inhibitory input from the striatum and excitatory signals from the subthalamic nucleus results in excitotoxicity with neuroinflammation in the SNpr situated remotely from the striatum [30,31]. The resulting chronic neurodegeneration persists even 91 days after the initial insult and is accompanied by regional neuronal loss with tissue shrinkage, and substantial neuroinflammation with the presence of macrophages, reactive microglia, and reactive astrocytes in the degenerating SNpr [32,33].…”

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders

“…Iron uptake, storage, and exportation within neuron, astrocytes, microglia, and oligodendrocyte are shown in the figure . may absorb iron in NTBI through mediation of DMT1 or ZIP14. 29,51 Iron export of astrocytes is mainly performed by FPN1 with the help of Cp. 52,53…”

“…Hence, iron may be absorbed by astrocytes through TF/TFR1 pathway and action of DMT1. Besides, astrocytes may absorb iron in NTBI through mediation of DMT1 or ZIP14 29,51 . Iron export of astrocytes is mainly performed by FPN1 with the help of Cp 52,53 …”