Iron is an essential element critical for a multitude of biological processes at the cellular level (including catalyzing essential enzymatic reactions and electron transport) and at the systemic level for oxygen transport in hemoglobin. Both iron excess and iron scarcity have important consequences. Excess iron accumulation leads to the production of dangerous free radical species, responsible for epithelium injury and increasing the risk for cancer, while iron deficiency is one of the most frequently observed diseases in the world today, affecting as many as two billion people. Therefore, iron levels need to be tightly regulated in the organism. This regulation is ensured by hepcidin, a 25 amino acid circulating peptide hormone sought for many years, whose role in maintaining systemic iron homeostasis was discovered by members of the team in 2001.

Mutations affecting hepcidin regulators or the hepcidin gene itself cause hemochromatosis, a common genetic disorder, characterized by excess iron overload of organs such as liver, heart, or pancreas. Accordingly, hepcidin knockout (KO) mice displayed iron overload (Lesbordes et al., Blood, 2006).

The discovery of hepcidin has brought a major contribution to the field of iron homeostasis. In the last two decades, hepcidin has been the focus of intense research, in order to clarify its role in iron homeostasis and in iron-related pathologies (Nemeth et al., Int J Mol Sci., 2021).

The majority of the studies on hepcidin focus on the liver, which is the major producer of the hormone. However, many cells and tissues express the hormone raising the possibility of hepcidin involvement at the single tissue level. In particular, we demonstrated for the first time hepcidin expression in myeloid cells infected in vitro and in vivo (Peyssonnaux et al., Blood, 2006). Concomitantly, a number of laboratories have shown that other tissues are able to synthesize hepcidin: heart, kidney, retina, brain, splenocyte, adipocytes, pancreas… The contribution of these tissues on circulating hepcidin and the specific function of hepcidin in these tissues were not known. In order to determine the role of these hepcidin-producing tissues, we have generated mice with floxed hamp1 alleles allowing tissue-specific gene deletion with the classical Cre-loxP strategy. Using this model, we demonstrated that hepcidin deletion specifically in the liver recapitulated characteristics of hemochromatosis, mimicking the iron overload phenotype of total hepcidin KO mice (Zumerle et al. Blood, 2014). More surprisingly, we found undetectable plasma hepcidin levels, indicating that cell types other than hepatocytes contribute in basal conditions negligibly to circulating hepcidin and suggesting novel, unanticipated roles, for locally produced hepcidin.

Originally identified as a cationic antimicrobial peptide (AMP) by its close structural similarity to the beta defensins, the expression and role of hepcidin in the intestine and skin, major sources of AMP production had never been investigated. We recently demonstrated that, in contrast to liver-derived hepcidin that acts as an endocrine hormone, hepcidin can be produced locally in these epithelia.