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Ironing out an approach to alleviate the hypoferremia of acute inflammation
Karin E. Finberg
Yale School of Medicine, New Haven, CT, USA E-mail: KARIN E. FINBERG - karin.finberg@yale.edu
doi:10.3324/haematol.2020.266627
In the steady state, iron levels in the plasma are regu- lated by the recycling of iron from senescent red blood cells by macrophages of the reticuloendothelial sys- tem. In systemic infections and inflammatory states, per- turbation of this process can result in hypoferremia (a decrease in circulating iron levels), which may represent a host defense mechanism to limit iron availability to pathogens.1 Because hypoferremia restricts the availabili- ty of iron to erythroid precursors, if sustained, it con- tributes to the development of the anemia of inflamma- tion. In this issue of Haematologica, Agoro et al.2 report that the acute hypoferremic response to lipopolysaccha- ride (LPS), a major component of the outer membrane of Gram-negative bacteria, is modulated in mice by pre- treatment with a truncated, C-terminal fragment of the hormone fibroblast growth factor 23.
During inflammatory states, iron is sequestered in cells due to a reduction in activity of ferroportin, the major cellular iron exporter that is expressed by multiple cell types, including macrophages.3 Activity of the ferro- portin transporter on cell membranes is regulated by hepcidin, the key iron regulatory hormone synthesized primarily by the liver; hepcidin occludes the ferroportin transporter and triggers its endocytosis and degradation.4 Hepcidin expression is induced in response to several proinflammatory cytokines, including interleukin-6 (IL- 6) and IL-1β, as well as LPS.1 In addition to its post-trans- lational regulation by hepcidin, ferroportin expression is regulated at the mRNA level by inflammatory stimuli. In macrophages, stimulation of toll-like receptor 4 (TLR4), a member of the pattern recognition receptor family, with LPS suppresses ferroportin mRNA and protein lev- els and also induces hepcidin expression.5 Stimulation of TLR2 and TLR6 also promotes ferroportin downregula- tion in a hepcidin-independent manner.6 In humans, LPS injection induces an acute rise in plasma cytokines such
as IL-6 and tumor necrosis factor (TNF), which is fol- lowed by hepcidin elevation, and ultimately a reduction
7
between inflammation, iron homeostasis, and fibroblast growth factor 23 (FGF23),8 a hormone that functions as a key regulator of phosphate and calcium homeostasis. FGF23 in the circulation appears to be mainly derived from bone, although FGF23 expression has also been detected in other tissues.9 Physiological actions of FGF23 are mediated through fibroblast growth factor receptors (FGFR) and by the co-receptor Klotho, which increases affinity of FGF23 for FGFR and is required for the hor- mone's ability to promote renal phosphate excretion.10 The phosphaturic activity of the mature, biologically- active FGF23 peptide can be abrogated by proteolytic cleavage at an RXXR motif located at the boundary between the FGF core homology domain and the 72- amino-acid C-terminal portion of FGF23.9 The isolated C- terminal FGF23 fragment (referred to here as C-FGF23) competes with full-length FGF23 for binding to the FGFR- Klotho complex, thereby impairing FGF23 signaling; accordingly, in healthy rodents, C-FGF23 administration inhibits renal phosphate excretion and induces hyper- phosphatemia.11
Circulating FGF23 levels are markedly elevated in chronic kidney disease,9 a condition in which disruption of systemic iron homeostasis, mediated by factors such as inflammation, therapy-related iron losses, decreased glomerular filtration rate, low serum erythropoietin (EPO), and elevated serum hepcidin, contributes to the development of anemia.12 Both iron deficiency and inflam- mation stimulate the production of FGF23 as well as its proteolytic cleavage.8 Interestingly, in mice with estab- lished chronic kidney disease (induced by subtotal nephrectomy), a single dose of C-FGF23 induced acute
in serum iron levels.
Recent studies have suggested intriguing crosstalk
haematologica | 2021; 106(2)