Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens.

Nramp1 (natural resistance-associated macrophage protein one) regulates intracellular pathogen proliferation and macrophage inflamma- tory responses. Murine Nramp1 exhibits a natural polymorphism with alleles termed resistant and susceptible. Alleles restrict or allow the prolifera- tion of intracellular pathogens, respectively. Struc- tural predictions suggest that Nramp1 encodes the prototypic member of a transporter family. Nramp1 exhibits sequence identity to Nramp2, which regu- lates intestinal and reticulocyte iron uptake. Based on this sequence identity we have initiated experi- ments for Nramp1 to investigate its role in macro- phage iron homoeostasis and using a transfection approach in the RAW264.7 murine macrophage- like cell line, which lacks a functional Nramp1 gene. Nramp1 expression supports increased acute cytoplasmic influx of iron, detected using the fluo- rescent iron sensor dye calcein. Analysis of the endogenous iron sensors, iron regulatory protein 1 and 2, reveals a greater flux of iron in Nramp1- expressing cells and in its exclusion from the cytoplasm. Other work supports the prediction that Nramp1 is a phosphoprotein and the extent of phosphorylation changes in response to inflamma- tory cytokines. Together these data support the hypothesis that control of intracellular iron ho- moeostasis is a vital element used by phagocytes to control the proliferation of intracellular pathogens. J. Leukoc. Biol. 66: 757-762; 1999.