Page 31 - 2020_02-Haematologica-web

Hepcidin and iron disorders
A
B
CD
Figure 2. The regulation of hepcidin expression (adapted from Silvestri et al.147). Schematic representation of a model of hepcidin regulation by two branches of the bone morphogenetic protein (BMP)-SMAD pathway, based on BMP knockout models,44,45,148 in (A) iron overload, (B) iron deficiency, (C) erythropoiesis expansion and (D) inflammation. According to a recent study BMP2 and BMP6 work collaboratively in vivo, possibly as a heterodimer.153 (A) BMP2 produced by liver endothelial cells (LSEC) binds BMP receptor type II, which phosphorylates the BMP receptors type I (ALK3) to activate SMAD1/5/8. The latter associated with SMAD4 translocate to the nucleus to bind BMP responsive elements (BRE) in the hepcidin promoter. In iron overload increased diferric transferrin displaces HFE from transferrin receptor (TFR) 1 to enable iron uptake and stabilizes surface TFR2 potentiating ALK3 signaling. Hemojuvelin (HJV) acts as a BMP co-receptor, while the function of the other hemochromatosis HFE and TFR2 proteins in the pathway activation is still unclear. Iron increases the production of BMP6 by LSEC, thereby activating ALK2 and likely also ALK3 (indicated by a dotted arrow) in the pathway. (B) In iron deficiency TMPRSS6, stabilized on the cell surface,149 cleaves HJV49 and inactivates the BMP2- ALK3 branch of the pathway. TFR2 is destabilized by the lack of diferric transferrin and HFE binds TFR1.150 The BMP6 pathway is inactive in the absence of the ligand and also because ALK2 is inactivated by FKBP12 binding.51 Together with epigenetic regulation,151 this suppresses hepcidin expression. (C) Erythropoiesis enhanced by erythropoietin consumes a large amount of iron: low serum iron (and diferric transferrin) suppresses the BMP2-ALK3 pathway,152 while BMP6 and other BMP are sequestered by erythroferrone (ERFE) released by erythroid cells.72,154 The result is hepcidin inhibition. (D) Schematic representation of hepcidin regulation by inflam- matory cytokines and of the pathogenesis of anemia of inflammation. Stimulated by inflammation [here indicated by lipopolysaccharide (LPS) through toll-like recep- tor 4 (TLR4)], macrophages produce interleukin-6 (IL6), which stimulates Janus kinase 2–signal transducer and activator of transcription 3 (JAK2-STAT3) signaling to upregulate hepcidin in association with the BMP-SMAD pathway.
haematologica | 2020; 105(2)
265