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Review
, 9 (2), 101-111

Iron and Inflammation - The Gut Reaction

Affiliations
Review

Iron and Inflammation - The Gut Reaction

Smriti Verma et al. Metallomics.

Abstract

Anemia is a frequent complication of many inflammatory disorders, including inflammatory bowel disease. Although the pathogenesis of this problem is multifactorial, a key component is the abnormal elevation of the hormone hepcidin, the central regulator of systemic iron homeostasis. Investigations over the last decade have resulted in important insights into the role of hepcidin in iron metabolism and the mechanisms that lead to hepcidin dysregulation in the context of inflammation. These insights provide the foundation for novel strategies to prevent and treat the anemia associated with inflammatory diseases.

Figures

Figure 1
Figure 1
Regulation of systemic iron homeostasis. Hepcidin, which is encoded by the hepcidin anti-microbial peptide (HAMP) gene, is produced by the liver in response to iron status and requirements. It down-regulates ferroportin (FPN) on macrophages and duodenal enterocytes to control the amount of iron entering the circulation from recycled red blood cells (RBCs) and the diet, respectively. Dietary ferric iron is reduced by the action of duodenal cytochrome B (DCytB), imported by divalent metal transporter-1 (DMT-1) expressed on the apical enterocyte membrane, and then exported at the basolateral membrane by FPN. Ferrous iron is converted into the ferric form by hephaestin (Heph) or ceruloplasmin (Cp) and transported in the circulation bound to transferrin (holo-transferrin). Similar transport mechanisms operate in the macrophage to recycle iron from RBCs.
Figure 2
Figure 2
Regulation of hepcidin expression in hepatocytes in response to iron status and requirements (left) or inflammation (right). Tissue iron increases the expression of bone morphogenetic protein 6 (BMP6), which acts on the BMP receptor (BMP-R) and co-receptor hemojuvelin (HJV). This interaction leads to the phosphorylation of the receptor-associated small-mothers against decapentaplegic (SMAD) 1/5/8 proteins, which then bind to SMAD4, translocate to the nucleus and up-regulate transcription of the HAMP gene to produce hepcidin. Plasma iron is sensed by the hemochromatosis protein HFE and the type 2 transferrin receptor (TfR2), leading to modulation of BMP/SMAD signals. Iron deficiency inhibits BMP/SMAD signals by inducing degradation of HJV, while erythropoiesis inhibits hepcidin expression through the action of erythroferrone. In inflammatory states, cytokines such as IL-6 and IL-22 act on their respective receptors to activate the Janus kinases (JAK)1/2, leading to phosphorylation and dimerization of signal transducer and activator of transcription 3 (STAT3). Dimeric STAT3 translocates to the nucleus to up-regulate HAMP transcription and increase hepcidin production. Activin B produced during inflammation increases HAMP transcription by activating the BMP/SMAD pathway. Additional inflammatory mediators, including other pro-inflammatory cytokines such as IL-1β, endoplasmic reticulum (ER) stress and agonists of innate pattern recognition receptors (PRRs), induce signals that activate other transcription (Tx) factors and up-regulate HAMP transcription.
Figure 3
Figure 3
Mechanisms involved in the pathogenesis of the anemia associated with inflammation. The figure shows the various factors that contribute to the development of anemia in the context of inflammation.

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