Iron homeostasis in host defence and inflammation

Abstract

Iron is an essential trace element for multicellular organisms and nearly all microorganisms. Although iron is abundant in the environment, common forms of iron are minimally soluble and therefore poorly accessible to biological organisms. Microorganisms entering a mammalian host face multiple mechanisms that further restrict their ability to obtain iron and thereby limit their pathogenicity. Iron levels also modulate host defence, as iron content in macrophages regulates their cytokine production. Here, we review recent advances that highlight the role of systemic and cellular iron-regulating mechanisms in protecting hosts from infection, emphasizing aspects that are applicable to human health and disease.

Figure 1. Iron homeostasis and its modulation by erythropoiesis and inflammation

Hepcidin blocks major iron flows into the plasma (predominantly from splenic macrophages recycling erythrocytes but also from duodenal absorption and from stores in hepatocytes) by causing degradation of its receptor, the iron exporter ferroportin. Hepcidin production by the liver is upregulated by increasing levels of plasma iron and liver iron stores. Infection and inflammation also stimulate transcription of the gene encoding hepcidin. By contrast, after erythropoietic stimulation, erythroid precursors secrete mediators (such as erythroferrone) that suppress hepcidin production in the liver. Thicker arrows indicate dominant flow of iron. IL-6, interleukin-6.

Figure 2. Regulation of HAMP transcription

The SMAD and signal transducer and activator of transcription 3 (STAT3) pathways are the main known regulators of transcription of the gene encoding hepcidin (HAMP) in response to iron-related and inflammatory signals. The SMAD pathway is activated by the interaction of bone morphogenetic protein 6 (BMP6) and other BMPs with a heterodimeric BMP receptor (BMPR) containing type 1 and type 2 subunits. Haemojuvelin (HJV) is an iron pathway-specific ligand of the BMPR and BMPs that increases BMPR signalling. Transmembrane protease serine 6 (TMPRSS6) is a negative regulator of iron-related BMPR signalling and acts by cleaving HJV. Neogenin may facilitate the interaction of HJV with TMPRSS6 and also perhaps with other components of the BMPR complex. The concentration of extracellular iron–transferrin is sensed by transferrin receptor 1 (TFR1) and TFR2 assisted by HFE, and HFE and TFR2 convey a stimulatory signal to the BMPR complex through interactions that have not yet been characterized. The BMPR phosphorylates regulatory SMADs (R-SMADs), which complex with SMAD4 to enter the nucleus and stimulate the transcription of HAMP. Inflammation increases HAMP transcription through increased levels of interleukin-6 (IL-6), activin B and other cytokines. IL-6 binds to the IL-6 receptor (IL-6R) and signals through Janus kinase 1 (JAK1)-induced phosphorylation of STAT3 and the binding of phosphorylated STAT3 to cognate motifs in the HAMP promoter. Activin B probably signals through the BMPR pathway. ERK, extracellular signal-regulated kinase.

Figure 3. Hepcidin-induced sequestration of iron in macrophages

The flow of iron in macrophages is depicted by dashed arrows. a | When hepcidin concentrations are low, ferroportin exports iron from macrophages, resulting in relative macrophage iron depletion. Low levels of intracellular iron stores (ferritin) are inhibitory to intracellular microorganisms, but higher extracellular iron levels may promote the growth of extracellular microorganisms. b | Increased hepcidin concentrations cause ferroportin degradation and iron sequestration by ferritin in macrophages, which restricts iron availability for extracellular microorganisms but may promote the growth of intracellular microorganisms. The favourable effect on intracellular microorganisms is opposed by local production of interferon-γ (IFNγ) and nitric oxide (NO), which stimulate transcription of the gene encoding ferroportin (SLC40A1) in an autocrine or paracrine manner.