Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Abstract

SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

Biomarkers in primary open angle glaucoma

“…A recent study found that Hep is expressed in M ü ller cells, photoreceptor cells, and retinal pigmented epithelium. The expression of Hep in the retina points to the local intraocular regulation of iron metabolism, separate from a dependence on the circulation liver-derived hormone: circulating Hep would likely be inaccessible to intraocular tissues due to the presence of blood-ocular barriers (99) . Recently, it was shown that local Hep secretions may have a pathogenic role in POAG (100) , however, the authors raised a number of questions that need to be elucidated before fi nal conclusions are drawn.…”

Induction of the Cystine/Glutamate Exchanger SLC7A11 in Retinal Pigment Epithelial Cells by the Antipsoriatic Drug Monomethylfumarate

“…32 Animals were weighed and anesthetized using 17 lL (1 lL/g body weight) of a solution of ketamine (80 mg/mL) and xylazine (12 mg/mL). Then 5 lL of proparacaine solution (5% w/v) was administered topically to the eyes.…”

Activated macrophages induce hepcidin expression in HuH7 hepatoma cells

“…8,9 Moreover, the absence or low expression of hepcidin is implicated in the etiology of hereditary hemochromatosis as a primary cause of iron overload 10 whereas its over-expression has been linked to iron deficiency anemia. 11 While a number of cell types are known to express hepcidin, [12][13][14][15][16] serum hepcidin levels are mainly determined by production and release of the peptide by hepatocytes; however, the involvement of other cell types in the regulation of hepatocyte hepcidin is unclear. Macrophages are primary candidates for such a role as they provide the majority of serum iron recycled from senescent erythrocytes and are also intrinsically involved in innate immunity and awakening of the adaptive immune response.…”