Inflammation alters the expression of DMT 1, FPN 1 and hepcidin, and it causes iron accumulation in central nervous system cells

Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores through modulation of iron regulatory proteins including hepcidin, FPN, ferritin, and DMT1.

“Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores by modulating the expression and activity of various iron regulatory proteins including hepcidin, FPN, ferritin, and the iron importer divalent metal transporter 1 (DMT1) [25–30].”

Hepcidin is produced in response to inflammation or other signals by heart cardiomyocytes and by brain astrocytes and microglia.

“Hepcidin is also produced in response to inflammation or other signals by heart cardiomyocytes (Merle et al., 2007) and by brain astrocytes and microglia (Urrutia et al., 2013).”

Localized targeting of hepcidin excess in the heart or brain may be important in the context of cardiovascular or neurodegenerative disorders.

“Considering that the hepcidin/ferroportin axis is crucial for cardiac function (Lakhal-Littleton et al., 2015) and that inflammatory induction of hepcidin causes iron accumulation in nervous system cells (Urrutia et al., 2013), localized targeting of hepcidin excess in the heart or brain may be important in the context of cardiovascular or neurodegenerative disorders.”

After 6 h, secreted hepcidin provoked a decrease of ferroportin in astrocytes, microglia, and neurons and an increase in DMT1 in microglia.

“After 6 h, secreted hepcidin provoked a decrease of ferroportin in astrocytes, microglia, and neurons and an increase in DMT1 in microglia.”

Changes in ferroportin concentrations do not necessarily change the efflux of iron from cells.

“These results suggest that changes in ferroportin concentrations do not necessarily change the efflux of iron from cells.”

The inflammatory-stimulus-induced iron accumulation is associated with changes in DMT1 and ferroportin; stimulated hippocampal neurons showed substantial increases in DMT1 and decreased concentrations of ferroportin, whereas microglia showed increased DMT1 protein concentrations but no changes in ferroportin.

“This accumulation is associated with changes in the two iron transporters, DMT1 and ferroportin; stimulated hippocampal neurons showed substantial increases in DMT1 and decreased concentrations of ferroportin, whereas microglia showed increased DMT1 protein concentrations but no changes in ferroportin.”

In-vitro short-term stimulation with tumour necrosis factor α, interleukin 6, or lipopolysaccharide for up to 18 h increases iron accumulation in neurons and microglia but not in astrocytes.

“In-vitro studies show that short-term stimulation (by use of tumour necrosis factor α, interleukin 6, or lipopolysaccharide) for up to 18 h increases iron accumulation in neurons and microglia (assayed by atomic absorption spectroscopy) but not in astrocytes.”

Hepcidin concentrations rapidly increased in astrocytes and microglia after activation with inflammatory stimuli, although hepcidin was undetectable in neurons.

“Moreover, hepcidin concentrations rapidly increased in astrocytes and microglia after activation with the inflammatory stimuli, although hepcidin was undetectable in neurons.”

Inflammatory stimuli and hepcidin induced iron accumulation in only neurons and microglia.

“To summarise, inflammatory stimuli and hepcidin induced iron accumulation in only neurons and microglia.36”

No change in iron content was detected in astrocytes after inflammatory stimulus, although DMT1 increased after stimulus, and only lipopolysaccharide induced a small decrease in ferroportin concentrations.

“No change in iron content was detected in astrocytes, although DMT1 increased after stimulus, and only lipopolysaccharide induced a small decrease in ferroportin concentrations.36”