An Inflammatory Pathway Mediating Rapid Hepcidin-Independent Hypoferremia

Hypoferremia represents an innate immune response to infection and inflammation sequestering iron from pathogens. The iron-hormone hepcidin is induced by such stimuli, causing degradation of the iron exporter ferroportin (Fpn) and reduced iron release from macrophages, suggesting that hepcidin is the crucial effector of inflammatory hypoferremia. Here we report the discovery of a fast, hepcidin-independent hypoferremia pathway. Stimulation of the toll-like receptor (TLR) 2 and TLR6 triggers profound decreases in Fpn mRNA and protein expression in bone marrow-derived macrophages, liver and spleen of mice without changing hepcidin expression. Furthermore, C326S Fpn knock-in mice with a disrupted hepcidin/Fpn regulatory circuitry respond to injection of the TLR2/6 ligand FSL1 by Fpn down regulation and a reduction of serum iron levels. Our findings challenge the prevailing role of hepcidin in hypoferremia, uncovering a rapid and potent inflammatory response pathway.