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C. Camaschella et al.
al iron deficiency. Adult Irp1-knockout mice have a nor- mal phenotype in basal conditions. Intestinal epithelium Irp1 and 2 deletion in adult mice leads to impaired iron absorption and local iron retention because of ferritin- mediated mucosal block.35
To escape IRP control, both enterocytes and erythroid cells also have a ferroportin isoform that, lacking the 5’ IRE, ensures iron export in iron deficiency while remain- ing sensitive to degradation by hepcidin.36
Ferritinophagy
In iron deficiency, cells may recover iron through fer- ritinophagy, a process mediated by the multifunctional protein NCOA4.25,26 First described as a transcriptional co- activator of androgen nuclear receptor, this protein is iron- regulated at the post-translational level. In iron-replete cells NCOA4 is bound by the E3 ubiquitin ligase HERC2 and degraded by the proteasome.37 In iron-deficient cells NCOA4 binds ferritin inducing its degradation. NCOA4 also controls DNA duplication origins and its loss in vitro predisposes cells to replication stress and senescence,38 coupling cell duplication and iron availability. Ncoa4- knockout mice accumulate ferritin in the liver and spleen, have reduced iron recycling and demonstrate increased susceptibility to iron-deficiency anemia.39 The high NCOA4 expression in erythroblasts24 suggested a role for ferritinophagy in hemoglobinization in vitro,24 in zebrafish embryos37 and in mice.40 However, the major relevance of the process is in iron-storing macrophages (Nai A. et al., unpublished data) contributing to systemic homeostasis.
Systemic iron homeostasis: the hepcidin-ferroportin axis
The identification of hepcidin was a breakthrough in understanding how the liver is the central regulator of iron homeostasis and how its deregulation leads to iron disorders. The 25 amino acid mature hepcidin peptide controls iron export to the plasma by inducing lysosomal degradation of the iron exporter ferroportin in entero- cytes, macrophages and hepatocytes;13 moreover, hep- cidin also occludes the central cavity that exports iron in ferroportin.41
Hepcidin transcription is upregulated in hepatocytes by circulating and tissue iron, through a crosstalk with liver sinusoidal endothelial cells, which produce the ligands (BMP6 and 2) that activate the hepatocyte BMP-SMAD pathway. BMP6 expression is regulated by iron,42 possibly in the context of an antioxidant response, controlled by NRF2.43 BMP2 is less iron sensitive and is highly expressed in basal conditions.44,45
Inflammatory cytokines such as interleukin (IL)-6 upregulate hepcidin expression by activating the IL-6R- JAK2-STAT3 pathway. High hepcidin levels induce iron retention in macrophages, high serum ferritin levels and iron-restricted erythropoiesis, all features of anemia of inflammation. For full hepcidin activation the IL-6 path- way requires functional BMP-SMAD signaling.46
Hepcidin expression is inhibited by iron deficiency, expansion of erythropoiesis, anemia/hypoxia, testos- terone and possibly other factors.1,47 The most powerful inhibitor is the liver transmembrane serine protease matriptase 2, encoded by TMPRSS6,48 which cleaves the BMP co-receptor hemojuvelin,49 thereby attenuating BMP-SMAD signaling and hepcidin transcription. The relevance of TMPRSS6 is highlighted by iron-refractory, iron-deficiency anemia (IRIDA), which results from
TMPRSS6 mutations in patients50 and inactivation in mice.48 Deregulated, persistently high hepcidin blocks iron entry into the plasma and leads to iron deficiency. Another local inhibitor, the immunophillin FKBP12, binds the BMP receptor ALK2, suppressing the pathway activa- tion.51
Erythroferrone (ERFE) is released by erythroid precursors stimulated by erythropoietin to suppress hepcidin expres- sion and favor iron acquisition for hemoglobin synthesis.52 In hypoxia hepcidin is also suppressed in vitro by soluble hemojuvelin, released by furin,53 an effect unclear in vivo, and by platelet-derived growth factor-BB in volunteers exposed to hypoxia.54 Proposed models of hepcidin regula- tion in different conditions are depicted in Figure 2A-D.
Macrophages produce hepcidin in inflammation, potentiating the systemic effect on iron sequestration.55
Local effects of hepcidin
As an antimicrobial peptide hepcidin is induced in the skin of patients with necrotizing fasciitis caused by group A streptococcal infections. Mice without hepcidin in ker- atinocytes fail to block the spread of infection because of a reduction of the neutrophils recruiting chemokine CXCL1.56
Cardiomyocytes produce hepcidin with local effect on ferroportin. Conditional cardiomyocyte hepcidin deletion in mice does not affect systemic iron homeostasis but leads to excess iron export, severe contractile dysfunction and heart failure.57
Emerging evidence links iron with lipid and glucose metabolism. Genome-wide association studies found overlapping associations for iron and lipid traits.58 Adipocytes produce hepcidin in severe obesity59 and hep- cidin and gluconeogenesis are concomitantly upregulated in conditions of insulin-resistance.60 Finally Tmprss6- knockout mice with high hepcidin levels are protected from obesity induced by a high-fat diet.61
Crosstalk between iron, oxygen and erythropoiesis
The hepcidin-ferroportin axis intersects other biological systems, such as IRP, hypoxia responsive pathways and erythropoietin signaling.
Iron absorption revisited
Iron absorption is a physiological example of crosstalk between IRP-hypoxia and the hepcidin-ferroportin axis. In the hypoxic duodenal environment, IRP1 controls transla- tion of hypoxia-inducible factor 2α (HIF-2α) which, stabi- lized by prolyl hydroxylase, upregulates the expression of apical (DMT1) and basolateral (ferroportin) enterocyte iron transporters.62 In iron deficiency, absorption is enhanced by hepcidin downregulation, which, favoring export, depletes enterocytes of iron, further stabilizing HIF-2α63 (Figure 1). In iron overload, high hepcidin increas- es enterocyte iron and impairs luminal uptake. In addition, the rapid cell turnover with shedding of ferritin-loaded enterocytes further limits iron absorption. In this way the interaction between local (hypoxia, IRP) and systemic (hepcidin) mechanisms optimizes iron balance.
Crosstalk between iron and erythropoiesis
Iron and erythropoiesis are interconnected at multiple levels and are reciprocally regulated. First, iron tunes renal production of erythropoietin, the growth factor essential for proliferation and differentiation of erythroid cells, The
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haematologica | 2020; 105(2)