Response: Monocyte hepcidin and the anemia of chronic disease

We appreciate the comments of our colleagues and agree with them that conditional knockouts of hepatocytes would be a pivotal tool to provide us with new information on the true role of monocyte-derived hepcidin for the control of body iron homeostasis under inflammatory conditions. An alternative approach would be to study this issue by functional knockout of monocytes using clodronate liposomes.

However, it has to be kept in mind that the amount of hepcidin produced by monocytes/macrophages is a magnitude lower than that reported for hepatocytes.¹  Thus, due to its low concentration, systemic effects on iron absorption as observed in transgenic or hepcidin knockout mice are unlikely to be exerted by monocyte-derived hepcidin.^2,3  Accordingly, the presumed function of monocyte hepcidin is to readily control ferroportin-mediated iron release by monocytes in an autocrine fashion, especially at sites of poor perfusion where circulatory hepcidin is not abundant. This may be part of a defense strategy of the body to limit iron availability for extracellular pathogens. In addition, cytokines produced by activated monocytes/macrophages such as interleukin (IL)-1β and IL-6 may further stimulate local formation of this peptide.

Further, our colleagues questioned why circulating ferritin levels were not correlated with hepcidin mRNA levels determined in monocytes of patients with anemia of chronic disease (ACD).⁴  Circulating ferritin concentrations under inflammatory conditions are the reflection of iron overload, the regulatory effects of cytokines on ferritin expression, and cellular apoptosis. Importantly, in contrast to hepcidin expression in the liver, this gene cannot be induced in monocytes or macrophages upon iron challenge,^1,4  which partly explains the lack of correlation. In addition, cytokines, which are known to strongly induce ferritin expression such as tumor necrosis factor-alpha, negatively affect hepcidin formation at least in hepatocytes.⁵  Whether this also applies to hepcidin induction of monocytes has to be shown. Animal models of anemia of chronic disease together with tissue-specific elimination of hepcidin and/or its regulatory molecules will be essential tools for acquiring deeper insights into the multiple roles of this small antimicrobial peptide during inflammatory processes.