Epidermal iron metabolism for iron salvage

Abstract

Background: The epidermis shows a reverse iron gradient from the basal layer to the stratum corneum and consequently, little epidermal intracellular iron is lost by desquamation.

Objective: To clarify the underlying mechanism of iron salvage.

Methods: We first used immunohistochemistry and mRNA quantification to demonstrate the distinctive expression pattern of iron metabolism molecules. The obtained results were confirmed using normal human epidermal keratinocytes (NHEKs) during in vitro differentiation. We next examined the effects of reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin on the intracellular iron content of cultured NHEKs. Finally, we compared epidermal and systemic iron metabolism between Fpn^Epi-KO mice and control mice.

Results: The results of both mRNA and protein expression analysis showed that most molecules participating in iron import and storage were expressed in the lower epidermis, while those involved in iron release from heme or iron transport were expressed in the upper epidermis. Consistent with their expression, keratinocyte differentiation reduced intracellular iron content. We next demonstrated that reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin significantly increased the intracellular iron content. Finally, we showed that the iron content of the epidermis and squames was significantly greater in Fpn^Epi-KO mice than in control mice, and that Fpn^Epi-KO exhibited a more rapid decrease in blood hemoglobin concentration than control mice on a low iron diet.

Conclusion: These studies demonstrated that the epidermis is equipped with a machinery by which intracellular iron in differentiated keratinocytes is excreted to the extracellular space before reaching the stratum corneum.

Keywords: Anemia; Epidermis; Ferroportin; Iron metabolism; Knockout mice; siRNA.