Hepcidin and Host Defense against Infectious Diseases

Abstract

Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses.

Fig 1. Overview of host iron homeostasis.

Iron is absorbed from the diet by duodenal enterocytes and transported into the bloodstream, where it is bound by transferrin. Most iron is incorporated into erythrocytes for heme synthesis. Splenic macrophages recover iron from senescent erythrocytes and release iron into circulation via ferroportin. Smaller amounts of iron are imported into other tissues as needed. Iron loss is not directly regulated and occurs through minor bleeding and shedding of duodenal enterocytes. Approximate iron content of adult human tissues is represented in parentheses.

Fig 2. The effect of hepcidin on iron homeostasis.

In the absence of hepcidin, iron absorbed from the diet by duodenal enterocytes is transported into the serum via ferroportin, and iron captured from senescent red blood cells is exported from splenic macrophages. In the presence of hepcidin, iron is retained in duodenal enterocytes, which eventually shed from the intestinal tract, blocking iron absorption from the diet. Mononuclear phagocytes retain and accumulate recycled iron rather than releasing it back into circulation, causing a drop in serum iron levels.

Fig 3. Mechanisms of hepcidin induction.

In hepatocytes, hepcidin induction is mediated primarily by BMP ligands binding with the HJV/BMPR complex. BMP6 is induced by high iron levels via an undefined mechanism. The protease TMPRSS6 inhibits hepcidin production by degrading HJV in response to low iron levels [95]. High holo-transferrin levels stabilize the transferrin receptor 2 (Tfr2)/HFE complex, which promotes hepcidin induction, possibly by direct binding with HJV or BMPR [100]. Hepcidin can also be induced by IL-6 via STAT3 signaling in hepatocytes and myeloid leukocytes. Inflammation can stimulate hepcidin production in myeloid leukocytes through pathogen recognition receptor signaling and through autocrine and paracrine production of IL-6.