Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Abstract

Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

Can Iron Treatments Aggravate Epistaxis in Some Patients With Hereditary Hemorrhagic Telangiectasia?

“…Additionally, hepcidin/ferroportin‐dependent mechanisms mean that iron deficient individuals generally absorb a higher proportion of ingested iron, and gastrointestinal absorption may be further enhanced in patients who are actively bleeding, or with cirrhotic liver diseases . In contrast, patients with chronic and/or inflammatory disease states with inappropriately elevated hepcidin have more limited gastrointestinal iron absorption, irrespective of ingested iron doses …”

“…65 In contrast, patients with chronic and/or inflammatory disease states with inappropriately elevated hepcidin have more limited gastrointestinal iron absorption, irrespective of ingested iron doses. 53,66…”

Quantitative data on the magnitude of the systemic inflammatory response and its relationship with serum measures of iron status

“…9 It is thought that hepcidin synthesis is influenced by cytokines such as interleukin 6 (IL 6), which promotes iron uptake by cells of the innate immune system. 10 Similar to hepcidin, the synthesis of CRP by hepatocytes is 5 driven by circulating IL 6. 11 In addition, albumin, although it is not directly involved in iron transport, is quantitatively the most important circulating binding protein, and is itself a negative acute phase protein commonly measured in clinical practice.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…In hepatocytes, it has been well‐documented that inflammation induces hepcidin gene expression via the interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) pathway, via iron sensing through the transferrin receptor 2 (TfR2)/human hemochromatosis protein (HFE), and the bone morphogenetic protein (BMP)/hemojuvelin (HJV)/SMAD (a small mothers of decapentaplegic protein) pathways, and downregulated by erythroferrone (ERFE) ‐dependent and ‐independent mechanisms . Recent studies have also demonstrated that hepcidin expression can be upregulated by progesterone and mifepristone, two steroid hormones, through cell surface protein progesterone receptor membrane component‐1, transforming growth factor β1, SMAD1/5/8‐independent signaling by activin B, oxidases such as NADPH‐dependent oxidase 4 or artificially overexpressed urate oxidase (UOX), IL‐1β via inducing CCAAT enhancer‐binding protein δ (C/EBPδ) expression, peroxiredoxin‐2 which is a supporter for STAT3 transcriptional activity, fibroblast growth factor‐encoding gene, and downregulated by the immunophilin FKBP12 (FK506‐binding protein 1A) via binding with BMP type I receptor ALK2, cystathionine β‐synthase, TfR1, and matriptase‐2 …”