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Abstract
The immune system and iron availability are intimately linked as appropriate iron supply is needed for cell proliferation, while excess iron, as observed in hemochromatosis, may reduce subsets of lymphocytes. We have tested the effects of a ferritin H gene deletion on lymphocytes. Mx-Cre mediated conditional deletion of ferritin H in bone marrow reduced the number of mature B cells and peripheral T cells in all lymphoid organs. FACS analysis showed an increase in the labile iron pool, enhanced reactive oxygen species formation and mitochondrial depolarization. The findings were confirmed by a B-cell specific deletion using Fthlox/lox; CD19-Cre mice. Mature B cells were strongly under-represented in bone marrow and spleen of the deleted mice, whereas pre-B and immature B cells were not affected. Bone marrow B cells showed increased proliferation as judged by the number of cells in S and G2/M phase as well as BrdU incorporation. Upon in vitro culture with B-cell activating factor of the tumor necrosis factor family (BAFF), ferritin H-deleted spleen B cells showed lower survival rates than wild type cells. This was partially reversed with iron-chelator deferiprone. The loss of T cells was also confirmed by a T cell-specific deletion in Fthlox/lox;CD4-Cre mice. Our data show that ferritin H is required for B and T cell survival by actively reducing the labile iron pool. They further suggest that natural B and T cell maturation is influenced by intracellular iron levels and possibly deregulated in iron excess or deprivation.
Highlights
All cells need iron for the de novo synthesis of heme, iron, or iron-sulfur cluster containing proteins
To test whether the development and homeostasis of hematopoietic cell lineages depend on ferritin, we analyzed bone marrow, thymus and spleen 30 days after Mx-Cre induced ferritin H (Fth) deletion
The deletion efficiency based on Fth mRNA was 8868% in the bone marrow, 7169% in thymus, and 8267% in spleen (Fig. 1E), in the range of previous studies [26,31,32]
Summary
All cells need iron for the de novo synthesis of heme-, iron-, or iron-sulfur cluster containing proteins This requires a cytoplasmic ‘‘labile iron pool’’ (LIP) of about 1 mM divalent iron [1]. In particular the syntheses of transferrin receptor 1 (TfR1), which functions in iron uptake, and ferritin H and L, which form the iron storage compartment to capture excess cytoplasmic iron, are adjusted to the LIP. This is achieved by the iron regulatory proteins 1 and 2, which bind to iron responsive elements on the respective mRNAs to control RNA translation and stability [3,4,5,6]. The steady state level of the LIP is maintained within a range that prevents damage, but ensures sufficient iron supply for biosynthetic pathways in the cytoplasm and mitochondria
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