Abstract
Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN). The hepatic iron-regulatory hormone hepcidin controls FPN internalization and degradation in response to bacterial infection. Salmonella typhimurium can invade macrophages and proliferate in the Salmonella-containing vacuole (SCV). Hepcidin is reported to increase the mortality of Salmonella-infected animals by increasing the bacterial load in macrophages. Here we assess the iron levels and find that hepcidin increases iron content in the cytosol but decreases it in the SCV through FPN on the SCV membrane. Loss-of-FPN from the SCV via the action of hepcidin impairs the generation of bactericidal reactive oxygen species (ROS) as the iron content decreases. We conclude that FPN is required to provide sufficient iron to the SCV, where iron serves as a cofactor for the generation of antimicrobial ROS rather than as a nutrient for Salmonella.
Highlights
Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN)
FPN remained with the Salmonella-containing vacuole (SCV) even at 12 h after infection in cells treated with FeSO4 (Supplementary Fig. 1)
Raw264.7 cells were pretreated with hepcidin, and infected with Salmonella coated with magnetite nanoparticles, which does not alter total FPN levels in the cell (Supplementary Fig. 2)
Summary
Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN). Hepcidin promotes the degradation of its receptor, the sole known cellular iron exporter ferroportin (FPN), resulting in iron retention by macrophages and reduction of intestinal iron absorption[2] This mechanism decreases the serum iron content to about 30% of its normal level, a physiological change known as hypoferremia of infection[4], which limits iron availability for extracellular bacteria and leads to increased iron storage in macrophages of the liver and spleen. 34 α-MHC I macrophages and a 50–100-fold decrease in bacterial cell numbers in the liver and spleen, resulting in increased survival of the mice This was interpreted as a typical representation of innate nutritional immunity, under the assumption that the iron status in the vacuoles in which Salmonella reside (SCV)[6] would be the same as in the macrophage cytosol. This effect was dependent on the presence of FPN in the SCV
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