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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

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Review

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Shane J F Cronin et al. Front Mol Biosci.

Abstract

Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.

Keywords: BH4; anemia; infection; iron; mitochondria.

Figures

Figure 1
Figure 1
Iron metabolism in the cell. Intracellular iron levels are strictly controlled as too little or too much can be detrimental to the health of the cell. Therefore, (1)-iron uptake, (2)-utilization, (3)-storage and (4)-export need to be managed in a coordinated manner, as well as the conversion between the oxidation states of iron (Fe2+ and Fe3+) in the cell. (1) Iron-bound transferrin (TF-Fe3+) and NTBI (non-transferrin-bound iron) are taken up into the cell by the iron importers DMT1 and ZIP14. STEAP3 is a ferrireductase which reduces Fe3+ to Fe2+, which can then be imported. (2) Once inside the cell, the bioavailable and more soluble Fe2+ is used for various biological processes– DNA replication, ROS production via Fenton/Haber-Weiss (F/H-W) chemistry, mitochondrial bioenergetics, Fe-S and heme biosynthesis, as well as a plethora of proteins which utilize the metal to carry out their functions. (3) Excess Fe2+ iron is dangerous due to its role in ROS production. Therefore, it needs to be stored but, at the same time, be readily available for use. This is achieved by a particular arrangement of ferritin proteins designated the “ferritin cage” which stores the more inert, insoluble Fe3+ form of iron. When intracellular levels are low, this ferritin cage is signaled for destruction by NCOA4 thus releasing the stored iron. (4) If intracellular iron levels are saturated, then the iron must be exported out of the cell. This is achieved by the iron exporter ferroportin (FPN). Once outside the cell the Fe2+ iron is oxidized to Fe3+ (via CP, HEPH, HEPHL). (5) Finally, Fe3+ iron is then bound to transferrin (Tf-Fe3+) and enters the circulation to begin the cycle again. Notably, hepcidin is an iron-controlling hormone produced by the liver. When systemic iron levels are high in the blood, hepcidin is produced and leads to the degradation of FPN on cells thus preventing cellular release of iron into the blood. Conversely, when iron blood levels are low, hepcidin expression is reduced.
Figure 2
Figure 2
Regulation of iron metabolism by IRP1. When cellular iron levels are low, Fe-S biogenesis in the mitochondria is reduced and IRP1 loses its Fe-S cluster component. This allows IRP1 to now bind to the IRE sequence in target mRNAs. IRP1 binds to the IREs at either the 3′ (for example transferrin mRNA) or 5′ (for example ferroportin mRNA) untranslated region (UTR) of the targeted mRNA. Binding to the 5′ UTR blocks translation while binding to the 3′ UTR stabilizes the mRNA against endonuclease cleavage. Thus, when iron levels are low (left panel), transferrin protein is enhanced while ferroportin protein is reduced resulting in increased iron import and reduced export, to ultimately increase intracellular iron levels. When iron levels are high (right panel), this leads to reduced iron uptake and increased export.
Figure 3
Figure 3
Essential role of iron for various cell types. Iron is needed by many different cell types to perform very distinct functions from oxygen carrying abilities of red blood cells (RBCs) to oxygen storage in muscle cells. Moreover, iron dysregulation has been observed in the pathogenesis of many diseases such as the neurodegenerative diseases Alzheimer's and Parkinson's. Importantly various immune cells regulate iron metabolism to induce their various effector functions. Notably, as iron is so essential for cell division, one of the earliest tasks of invading pathogens is to capture host iron in the circulation to aid their own growth and expansion. Therefore, restricting free iron is a first line of defense against invading pathogens.
Figure 4
Figure 4
BH4 enhances iron-dependent mechanisms upon T cell activation. Upon T cell receptor (TCR) stimulation, T cells alter their metabolic programming, such as promoting energy-producing mitochondria and electron transport chain (ETC) activity, to be able to proliferate and carry out effector functions. These increased metabolic needs require additional regulators for efficient ETC function to limit dangerous ROS byproducts due to the increased energy demands. To accomplish this, T cells induce the expression of the enzyme GCH1 which produces the metabolite BH4 after stimulation. BH4 can not only act as a superoxide ROS scavenger but also directly reduce Fe3+ to Fe2+ and therefore affect cytochrome C (cyto-C) activity in the ETC. Other iron-regulated processes such as heme and Fe-S biogenesis, as well as the function of various iron-dependent metalloproteins, may also be affected. Under BH4 deficiency, T cells show dysfunctional ETC, enhanced ROS, and reduced ATP production in activated T cells. Moreover, the T cells show dysregulated Mitoferrin, Frataxin, HO-1, Ferritin and overall reduced iron levels in the cell suggesting that BH4 deficiency affects iron metabolism and the cell compensates by trying to increase Fe2+ levels in the mitochondria. GTP, guanosine triphosphate; PTPS, 6-pyruvoyl tetrahydropterin synthase; SPR, sepiapterin reductase; DHTP, dihydroneopterin triphosphate; 6-PTH, 6-pyruvoyl tetrahydropterin; BH4, tetrahydrobiopterin; ROS, reactive oxygen radicals; ALAS, aminolevulinic acid synthase; e-, electron.

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