MACROPHAGE-HFE IS CRITICAL FOR LIPOPOLYSACCAHRIDE (LPS)-CONTROLLED HEPATIC HEPCIDIN ACTIVATION
Maja Vujic Spasic 1,2, Richard Sparla1,2, Jens Stolte3, Matthias W. Hentze2,3, Martina U. Muckenthaler1,2
1University Hospital of Heidelberg, Germany, 2Molecular Medicine Partnership Unit, 3European Molecular Biology Laboratory, Heidelberg, Germany
Systemic iron homeostasis is disrupted in the common, potentially fatal iron overload disorder hereditary hemochromatosis (HH). Mutations in the HFE/Hfe gene cause the most prevalent form of HH, hallmarked by inadequate expression of the Hepcidin, the key regulator of systemic iron homeostasis. To identify where Hfe acts to prevent HH, mice with tissue-specific Hfe ablation in hepatocytes, enterocytes and macrophages were generated. We uncovered that Hfe acts in hepatocytes to control systemic iron levels and Hepcidin expression, classifying genetic hemochromatosis as a liver disease.
While inappropriately low Hepcidin levels contribute to iron overload, increased Hepcidin expression plays an important role in the anaemia of inflammation (AI). Inflammation influences iron balance in the whole organism by reducing duodenal iron absorption and increasing macrophage iron retention resulting in low serum iron concentrations. Cytokine-mediated Hepcidin stimulation plays a critical role in this process. In Hfe-deficient mice the inflammatory response of Hepcidin is deregulated: while Hfe-/- mice mount a general inflammatory response following the injection of LPS (5μg) they fail to appropriately elevate Hepcidin mRNA expression and reduce serum iron levels.
It is however unclear how Hfe contributes to LPS-mediated Hepcidin induction in the liver and whether Hfe expression in hepatocytes, and/or liver macrophages, and/or other cell types is required. To answer this question, we injected constitutive, hepatocyte- and macrophage-specific Hfe mutant mice with LPS (5μg) for 8h. While LPS injections cause significant Hepcidin induction in Wt and hepatocyte-specific Hfe mutant mice, Hepcidin mRNA expression fails to be increased in macrophage-specific Hfe mutant mice.
This work demonstrates that Hfe expression in hepatocytes serves to maintain physiological Hepcidin expression and cellular/systemic iron homeostasis. By contrast, Hfe expression in macrophages is indispensable for the LPS-stimulated Hepcidin response. This study for the first time provides evidence for a role of Hfe in macrophages and innate immunity.