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Editorials
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complex with SMAD4, translocate to the hepatocyte nucleus, and bind to the BMP-RE to induce hepcidin expression. Holo-transferrin concentrations, which are sensed by the TfR1/HFE and TfR2 proteins on hepato- cytes, are also thought to modulate the same BMP signal- ing pathway in these cells. Low iron stores and low circu- lating iron (observed in the IDA group in this study), would result in decreased BMP signaling and a low level of hepcidin transcription. Low hepcidin would then allow for increased iron absorption and mobilization from stores. However, in the presence of infection, increased iron bioavailability becomes a liability, as pathogens also require iron for proliferation and survival. As part of the host defense, hepcidin is induced by infection and inflam- mation to limit iron availability to pathogens. Hepcidin regulation by infection and inflammation is mediated in large part by IL-6.14 IL-6 binding to its receptor, IL-6Rα, and co-receptor, gp130, results in phosphorylation of JAK1/2 in hepatocytes, which then phosphorylates STAT3. This then dimerizes and translocates to the nucle- us to induce hepcidin expression.
Importantly, the BMP pathway was shown to synergize with STAT3 pathway to induce hepcidin transcription.
Fiure 1. The design (A) and results (B) of the prospective study in women by Stoffel et al.7 The study evaluated the relative contribution of iron deficiency anemia and acute inflammato- ry stimuli on iron homeostasis. h: hours; d: day.
Disruption of BMP-RE in a liver cell line impaired hep- cidin response to IL-6.15 Studies using mouse models have demonstrated that hepcidin induction in response to inflammation is blunted when hepatic BMP signaling is genetically disrupted.16-20 Absence of HJV or ALK3 pre- vented induction of hepcidin in vivo following acute inflammatory stimulus (LPS or IL-6).17 Similarly, in Hfe and Tfr2 knockout mice, hepcidin induction in response to LPS was also blunted.16 Although these mouse studies did not model iron-deficiency anemia, such as was seen in the study subjects in Stoffel et al.7 they provided the proof of principle that the BMP pathway plays an important role in hepcidin responsiveness to inflammation.
However, it remains to be determined whether the pre- sumed decrease in BMP-SMAD signaling in the study subjects is caused by iron deficiency, or by anemia and increased erythropoietic activity, or the combination of these factors. Anemia induces erythropoietin (EPO) secre- tion by the kidneys.21 EPO in turn acts on the bone mar- row erythroblasts to induce expression of erythroferrone (ERFE),22 and ERFE is shown to function as a BMP trap to suppress hepcidin.23 Although EPO was elevated in IDA subjects in this study, serum ERFE levels were not meas-
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haematologica | 2019; 104(6)