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.
Highlights
Iron is one of the most abundant elements on Earth and essential to almost all organisms
We demonstrated that human peripheral blood mononuclear cells (PBMCs) when stimulated through the T cell receptor (TCR) produce BH4 and that QM385-mediated inhibition of BH4 diminished the proliferative capacity of healthy human donor T cells (Cronin et al, 2018)
In this review we have highlighted the major pathways and immune cells involved in iron regulation, from initial uptake in the gut to the utilization of iron for Fe-S clusters, heme biogenesis and mitochondrial function
Summary
Iron is one of the most abundant elements on Earth and essential to almost all organisms. Fe2+ iron is chaperoned to the basolateral surface of the cell by PCBP2 (poly-(rC)-binding protein 2) where the iron is released into the circulation for systemic use (Yanatori et al, 2016) This latter step is controlled by the iron exporter, ferroportin (FPN, called SLC40A1) followed by extracellular oxidation to ferric iron by the copper enzyme hephaestin (HEPH) (Vulpe et al, 1999; Muckenthaler et al, 2017). Transferrin (Tf) is a glycoprotein containing two high affinity binding sites for ferric iron (Fe3+) (Aisen et al, 1978), which captures Fe3+ in the circulation (Figure 1) This diferric Tf conjugate (Tf-Fe3+) prevents free, non-transferrin bound iron (NTBI), from engaging in Fenton chemistry to produce dangerous hydroxyl radicals, and deprives invading pathogens of free iron to block their expansion and proliferation (Barber and Elde, 2014).
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