Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non–transferrin-bound iron

D Stefanova, A Raychev, J Arezes… - Blood, The Journal …, 2017 - ashpublications.org
D Stefanova, A Raychev, J Arezes, P Ruchala, V Gabayan, M Skurnik, BJ Dillon, MA Horwitz
Blood, The Journal of the American Society of Hematology, 2017ashpublications.org
The iron-regulatory hormone hepcidin is induced early in infection, causing iron
sequestration in macrophages and decreased plasma iron; this is proposed to limit the
replication of extracellular microbes, but could also promote infection with macrophage-
tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host
defense, and the spectrum of microbes affected, are poorly understood. Using mouse
models, we show that hepcidin was selectively protective against siderophilic extracellular …
Abstract
The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non–transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus. Hepcidin analogs may be useful for treatment of siderophilic infections.
ashpublications.org