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Originally published online as doi:10.1189/jlb.1107781 on June 27, 2008

Published online before print June 27, 2008
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(Journal of Leukocyte Biology. 2008;84:689-700.)
© 2008 by Society for Leukocyte Biology

The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial-containing phagosome

Kristopher E. Van Zandt*,{dagger}, Fatoumata B. Sow*,{dagger}, William C. Florence*,{dagger}, Bruce S. Zwilling*,{dagger}, Abhay R. Satoskar*,{dagger}, Larry S. Schlesinger*,{dagger},{ddagger},§ and William P. Lafuse{dagger},{ddagger},1

* Departments of Microbiology,
{ddagger} Molecular Virology, Immunology and Medical Genetics, and
§ Internal Medicine, Division of Infectious Diseases, and
{dagger} Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA

1 Correspondence: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210, USA. E-mail: lafuse.1{at}osu.edu

ABSTRACT

Intracellular pathogens, including Mycobacterium tuberculosis, obtain iron from the host for their survival. Ferroportin 1 (FPN1; SLC40A1) is the sole iron exporter from mammalian cells and is expressed in the duodenum and macrophages. In the present study, we show that FPN1 mRNA levels in the mouse macrophage cell line RAW264.7 are synergistically induced by treatment with live or {gamma}-irradiated M. tuberculosis and IFN-{gamma}. FPN1 mRNA levels were also induced by Mycobacterium avium and IFN-{gamma} in RAW264.7 cells and the mouse alveolar macrophage cell line AMJ2-C8. Treatment of mouse resident peritoneal macrophages with M. tuberculosis and IFN-{gamma} resulted in a sixfold increase in FPN1 mRNA expression. In contrast, M. tuberculosis and IFN-{gamma} inhibited FPN1 mRNA expression in bone marrow-derived macrophages and lung macrophages, which have high basal levels of FPN1 mRNA expression. Using confocal microscopy, FPN1 protein localized rapidly to M. tuberculosis phagosomes after infection in RAW264.7 macrophages. In RAW264.7 cells expressing wild-type natural resistance-associated macrophage protein 1 (Nramp1Gly169), FPN1 and Nramp1 partially colocalized in late endosomes/lysosomes prior to infection. After 2 h of infection, Nramp1 and FPN1 were present in M. tuberculosis phagosomes. Our studies provide evidence for transcriptional regulation of FPN1 by pathogenic mycobacteria and IFN-{gamma}, which is dependent on the macrophage type. The trafficking of FPN1 to the M. tuberculosis phagosome suggests that it is involved in regulating iron availability to the mycobacteria in this locale.

Key Words: FPN1 • Mycobacterium tuberculosis • IFN-{gamma}