Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

Abstract

In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis.We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and ␤-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis. (Blood. 2011;117(4):1379-1389) IntroductionIron metabolism and erythropoiesis are closely related. Delineating the mechanisms by which they cooperate and coregulate is crucial to understand a variety of vital physiologic functions. Erythropoiesis modulates iron absorption by participating in the regulation of hepcidin, 1-3 a peptide hormone produced mainly in the liver. 4,5 Hepcidin controls iron absorption and recycling by inducing internalization and degradation of ferroportin (Fpn1), the only known cellular iron exporter. 6 Iron demand increases with erythropoietic activity, strongly down-regulating hepcidin expression [1][2][3] and allowing for increased iron flow to the serum. In addition to being regulated by erythropoiesis, hepcidin expression also responds to hypoxia, iron levels, and inflammation. 2 While erythropoiesis and hypoxia block hepcidin expression, inflammation and high iron levels increase it. Thus, modulation of this peptide hormone requires integration of opposing stimuli. 7 Indeed, the effect of erythropoiesis can be partially impaired by iron overload and inflammation. 7 HFE, the gene mutated in most cases of hereditary hemochromatosis (HH), 8,9 is thought to participate in hepcidin regulation in response to iron. 10 Iron overload in this disorder results from a failure to regulate iron absorption despite an increased iron load, leading to abnormal iron deposition in key organs if left untreated. Abnormally low hepcidin expression seems to be the major factor leading to iron overload in HH, 11-13 although the exact molecular mechanism is sti...

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

“…However, increased erythrocytes and hemoglobin were not observed in 2-month Hepc KO mice in a previous study. 44 Hemoglobin and erythrocyte number declined significantly in mice of both genotypes with age, but the magnitude of the reduction in hemoglobin was significantly less for aging Hepc KO mice than for WT mice ( …”

Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

“…Phlebotomy is the only treatment option, while iron chelation therapies are extremely rare and controversial (44,45). However, phlebotomy increases erythropoiesis to compensate for blood loss, and Hamp levels are further suppressed by high erythropoietic activity, thereby leading to more dietary iron absorption (23,46). This may lengthen the duration of the "de-ironing" stage after initial diagnosis of HFE-related hemochromatosis, due to very frequent phlebotomies (weekly phlebotomy for 3 months to a year) (47).…”

“…Mutations in the HFE gene are associated with the most frequent form of hereditary hemochromatosis, which results from a failure to upregulate HAMP and downregulate iron absorption despite an increased iron load (22,23). HFE-related hemochromatosis, if left untreated, causes abnormal iron deposition in key organs, leading to liver fibrosis, cirrhosis, congestive cardiomyopathy, and diabetes (24).…”

Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

“…In addition, TFR-2 was discovered to be associated to erythropoietin receptor (Epo-R) in the EpoR complex, and thus to exhibit an extra-hepatic function, being required for efficient erythroid differentiation and erythropoiesis (Forejtnikova, Vieillevoye et al 2010). Furthermore, very recently it has been demonstrated that also HFE is expressed in erythroblast and plays a role in the regulation of erythroid www.intechopen.com differentiation, and that HFE deficiency is associated with increased erythropoiesis partly due to enhanced iron absorption and delivery to the erythron due to decreased hepcidin levels and increased TSAT, and partly due to a direct effect of HFE on the modulation of iron uptake in erythroid cells (Ramos, Guy et al 2011). These new exciting findings suggest that the TFR-2/HFE complex is directly involved in the regulation of erythropoiesis independently of hepcidin levels, and thus that genetic variations of HFE and TFR-2 may influence RBCs production and the development of anemia in conditions characterized by reduced iron availability, such as CHD.…”