Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders  Caiyi Wang, Zheng Fang, Zesen Zhu, Jing Liu, Huiyong Chen  Experimental Hematology  Volume 52, Pages 24-31 (August 2017) DOI: 10.1016/j.exphem.2017.05.002 Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Reciprocal regulation between hepcidin and erythropoiesis. (A) Excess hepcidin decreases iron available for erythropoiesis. When hepcidin is elevated in IRIDA or chronic diseases (e.g., inflammation, infection, or cancer), circulating iron is decreased because of the suppression of intestinal iron absorption, impaired iron release from hepatic stores, and reduced iron recycling from splenic macrophages. This process reduces the amount of iron available for erythropoiesis, resulting in anemia. (B) Erythropoiesis decreases hepcidin to increase iron availability for erythropoiesis. When erythropoiesis is stimulated, erythroid cells may secrete factors, such as GDF11, GDF15, TWSG1, and ERFE, to decrease hepcidin production by hepatocytes, thus increasing iron absorption in the intestine, iron release from the spleen and liver, and circulating iron. If stimulated erythropoiesis is sustained, iron overload can occur. Experimental Hematology 2017 52, 24-31DOI: (10.1016/j.exphem.2017.05.002) Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Promoter elements and signaling pathways that regulate HAMP gene transcription. The HAMP gene promoter region includes the positive regulatory elements STAT3RE, BMPRE, C/EBP, and CRE in addition to the negative regulatory element HRE. The extracellular signaling molecule BMP binds to its receptor BMPR, resulting in the phosphorylation of intracellular Smad1/5/8. The phosphorylated Smad1/5/8 complexes with Smad4 and translocates to the nucleus, where it stimulates the transcription of HAMP by binding at the promoter element BMPRE. The BMP–Smad pathway is also positively regulated by the BMP co-receptor HJV. The transmembrane serine protease TMPRSS6 can cleave HJV on the membrane surface, suppressing signaling through the BMP–Smad signaling pathway and thus resulting in reduced transcription of HAMP. The binding of the inflammatory cytokine IL-6 to its cell surface receptor ILR induces a signaling cascade, leading to the activation of intracellular JAK2 kinase. Activated JAK2 catalyzes STAT3 phosphorylation and causes its binding to STAT3RE, mediating the transcriptional activation of HAMP. Hypoxia contributes to the stabilization of HIF protein, which binds to HRE and inhibits HAMP transcription. Hypoxia also promotes the synthesis of the platelet-derived growth factor PDGF-BB, which inhibits the synthesis of the transcription factor CREB/CREBH, reducing HAMP transcription. Erythroid factors, such as ERFE, GDF15, GDF11, and TWSG1, are identified to inhibit hepcidin production. ERFE may function through TMPRSS6 involved in the BMP–Smad pathway. The mechanisms underlying the effects of GDF15 and GDF11 on hepcidin remain unknown. TWSG1 works as an antagonist of BMPs to inhibit the BMP–Smad pathway, thereby reducing hepcidin synthesis. EPO may also decrease the binding of the transcription factor C/EBPα to the element C/EBP to inhibit HAMP transcription. Positive regulatory elements, including STAT3RE, BMPRE, C/EBP, and CRE, are in solid boxes. The negative regulatory element HRE is in the dashed box. ATG = Translation initiation codon; TSS = transcription initiation site. Experimental Hematology 2017 52, 24-31DOI: (10.1016/j.exphem.2017.05.002) Copyright © 2017 ISEH - International Society for Experimental Hematology Terms and Conditions