AUTHOR=Willemetz Alexandra , Beatty Sean , Richer Etienne , Rubio Aude , Auriac Anne , Milkereit Ruth J. , Thibaudeau Olivier , Vaulont Sophie , Malo Danielle , Canonne-Hergaux François 

TITLE=Iron- and Hepcidin-Independent Downregulation of the Iron Exporter Ferroportin in Macrophages during Salmonella Infection

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00498

DOI=10.3389/fimmu.2017.00498

ISSN=1664-3224

ABSTRACT=<p>Retention of iron in tissue macrophages <italic>via</italic> upregulation of hepcidin (HAMP) and downregulation of the iron exporter ferroportin (FPN) is thought to participate in the establishment of anemia of inflammation after infection. However, an upregulation of FPN has been proposed to limit macrophages iron access to intracellular pathogens. Therefore, we studied the iron homeostasis and in particular the regulation of FPN after infection with <italic>Salmonella enterica</italic> serovar Typhimurium in mice presenting tissue macrophages with high iron (AcB61), basal iron (A/J and wild-type mice), or low iron (<italic>Hamp</italic> knock out, <italic>Hamp</italic><sup>−/−</sup>) levels. The presence of iron in AcB61 macrophages due to extravascular hemolysis and strong erythrophagocytosis activity favored the proliferation of <italic>Salmonella</italic> in the spleen and liver with a concomitant decrease of FPN protein expression. Despite systemic iron overload, no or slight increase in <italic>Salmonella</italic> burden was observed in <italic>Hamp</italic><sup>−/−</sup> mice compared to controls. Importantly, FPN expression at both mRNA and protein levels was strongly decreased during <italic>Salmonella</italic> infection in <italic>Hamp</italic><sup>−/−</sup> mice. The repression of <italic>Fpn</italic> mRNA was also observed in <italic>Salmonella</italic>-infected cultured macrophages. In addition, the downregulation of FPN was associated with decreased iron stores in both the liver and spleen in infected mice. Our findings show that during <italic>Salmonella</italic> infection, FPN is repressed through an iron and hepcidin-independent mechanism. Such regulation likely provides the cellular iron indispensable for the growth of <italic>Salmonella</italic> inside the macrophages.</p>