Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway

Hepcidin is a small peptide hormone produced by the liver, which ensures for a tight balance of systemic and cellular iron levels in the body. Although its function appeared to be related to drosophila’s antimicrobial peptides like defensins, hepcidin is nowadays established as the key systemic regulator of iron homeostasis. Hepcidin orchestrates systemic iron fluxes by blocking iron absorption form the duodenum and iron release from macrophages. It does so by binding to ferroportin, the sole iron-exporter predominantly expressed on macrophages and enterocytes, causing its internalization, degradation and subsequent iron retention within the macrophages . The principal function of hepcidin in the regulation of systemic iron levels has been revealed using genetically engineered mouse models with overexpression or loss-off hepcidin function. Lack of hepcidin expression or mutations affecting regulators of hepcidin expression (e.g. Hfe) cause hemochromatosis, a common genetic iron overload disorder.

Although hepcidin is produced mainly by the hepatocytes, many other cells/tissues are able to synthesize the hormone. However, the exact physiological role of the extra-hepatocytic hepcidin is still unknown. For example, it was shown that increased hepcidin expression by macrophages contributed to down regulation of ferroportin protein levels in an autocrine manner.