Non-Transferrin-Bound Iron (NTBI) Uptake by T Lymphocytes: Evidence for the Selective Acquisition of Oligomeric Ferric Citrate Species

Joao Arezes,Matthijn Vos,Vera Dias,Xiao L Kong,Maria Rangel,Ines Vieira,Robert C Hider,Monica Costa,Rui Fernandes,Anna Carlsson,Graça Porto,Jorge P Pinto,Yuri Rikers

doi:10.1371/journal.pone.0079870

Abstract

Iron is an essential nutrient in several biological processes such as oxygen transport, DNA replication and erythropoiesis. Plasma iron normally circulates bound to transferrin. In iron overload disorders, however, iron concentrations exceed transferrin binding capacity and iron appears complexed with low molecular weight molecules, known as non-transferrin-bound iron (NTBI). NTBI is responsible for the toxicity associated with iron-overload pathologies but the mechanisms leading to NTBI uptake are not fully understood. Here we show for the first time that T lymphocytes are able to take up and accumulate NTBI in a manner that resembles that of hepatocytes. Moreover, we show that both hepatocytes and T lymphocytes take up the oligomeric Fe3Cit3 preferentially to other iron-citrate species, suggesting the existence of a selective NTBI carrier. These results provide a tool for the identification of the still elusive ferric-citrate cellular carrier and may also open a new pathway towards the design of more efficient iron chelators for the treatment of iron overload disorders.

Highlights

Iron, the most abundant transition metal in mammalian systems, is essential for metabolic processes, including molecular oxygen transport and DNA synthesis
In the present study we provide, for the first time, evidence demonstrating that T lymphocytes are able to take up and accumulate non-transferrinbound iron (NTBI) and that, like hepatocytes, selectively uptake a unique oligomeric ferric citrate species in conditions mimicking those observed during iron overload disorders, suggesting the existence of a selective NTBI carrier
Taking advantage of the recent development of a speciation model for Fe-citrate [22], we investigated iron uptake by hepatocytes and T lymphocytes in the presence of various Fe:citrate ratios, for which the model predicts the formation of distinct Fe-citrate species

Summary

Introduction

The most abundant transition metal in mammalian systems, is essential for metabolic processes, including molecular oxygen transport and DNA synthesis. Even the robust hepatocyte has a threshold beyond which iron accumulation becomes toxic, leading to the development of liver pathologies such as fibrosis, cirrhosis and hepatocarcinoma. These conditions are hallmarks of iron overload disorders, including beta-thalassemia and hereditary hemochromatosis. In the present study we provide, for the first time, evidence demonstrating that T lymphocytes are able to take up and accumulate NTBI and that, like hepatocytes, selectively uptake a unique oligomeric ferric citrate species in conditions mimicking those observed during iron overload disorders, suggesting the existence of a selective NTBI carrier

Methods

Results

Conclusion