The second transferrin receptor regulates red blood cell production in mice

Transferrin receptor 2 (TFR2) contributes to hepcidin regulation in the liver and associates with erythropoietin receptor in erythroid cells. Nevertheless TFR2 mutations cause iron overload (hemochromatosis type 3) without overt erythroid abnormalities. To clarify TFR2 erythroid function, we generated a mouse lacking Tfr2 exclusively in the bone marrow (Tfr2BMKO). Tfr2BMKO mice have normal iron parameters, reduced hepcidin levels, higher Hb and RBC and lower MCV than normal control mice, a phenotype that becomes more evident in iron-deficiency. In Tfr2BMKO mice the proportion of nucleated erythroid cells in the bone marrow is higher and the apoptosis lower than in controls, irrespective of comparable erythropoietin levels. Induction of moderate iron-deficiency increases erythroblasts number, reduces apoptosis and enhances Epo levels in controls, but not in Tfr2BMKO mice. Epo target genes such as Bcl-xL and Epor are highly expressed in the spleen and in isolated erythroblasts from Tfr2BMKO mice. Low hepcidin expression in Tfr2BMKO is accounted for by erythroid expansion and production of the erythroid regulator erythroferrone. We suggest that Tfr2 is a component of a novel iron sensing mechanism that adjusts erythrocyte production according to iron availability likely by modulating the erythroblast Epo sensitivity.