Nramp1 modulates iron homoeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de- acidification of intracellular vesicles

Biggs, T.E., Baker, S.T., Botham, M.S., Dhital, A., Barton, C.H. and Perry, V.H. (2001) Nramp1 modulates iron homoeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de- acidification of intracellular vesicles. European Journal of Immunology, 31 (7), 2060-2070. (doi:10.1002/1521-4141(200107)31:7<2060::AID-IMMU2060>3.0.CO;2-L).

Abstract

Nramp1 controls responses to infection and encodes a biallelic (G169D) macrophage-restricted divalent-cation transporter. Nramp1D169 is phenotypically null.We demonstrate Nramp1 is implicated in iron regulation in vivo. In spleen, expression is exclusive to Nramp1G169 strains within the red pulp. By morphometric analysis, the distribution of splenic iron, following systemic overload, correlates with Nramp1 genotype. More iron is located within the red pulp in Nramp1D169 strains, whereas in Nramp1G169 strains iron deposits are localized within the marginal-zone metallophilic cells. Nramp1 immunoreactive protein is not present in control brain, but inducible within a hemorrhagic lesion model in Nramp1G169 strains. Nramp1 protein expression demonstrates an inverse correlation to the presence of iron. Nramp1G169 strains show no Perl's stain-reactive iron within the lesion. In contrast, Nramp1D169 strains display iron-staining cells. The process of cellular iron regulation was investigated in vitro in Nramp1G169 transfectant Raw264.7 macrophages. Greater (30-50%) iron efflux from Nramp1G169 compared with Nramp1D169 cells was determined. The extent of Nramp1-dependent iron-release was influenced by bafilomycin A1, and endogenous nitric oxide synthesis, both inhibitors of vacuolar-ATPase. This study demonstrates that Nramp1 regulates macrophage iron handling, and probably facilitates iron release from macrophages undergoing erythrophagocytosis in vivo.

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