Fig 1.
Commercial iron formulations do not transport iron across a BBB model.
Using the bichamber model of the BBB, H-ferritin and Tf robustly transport iron across the huECs at each time point. Minimal iron transport is observed for the 5 commercial iron formulations. The concentration of the commercial formulations, Tf and H-ferritin was 300 μg/ml. All values are means ± SD, with statistical significance evaluated against the untreated control using two-way ANOVA and Bonferroni’s post hoc comparisons. * = p<0.05, *** = p<0.001.
Fig 2.
Transferrin and H-ferritin transport of iron is responsive to signaling by apo- and holo-Tf.
A) Apo-Tf in the basal chamber increases the amount of iron transported across the endothelial cells by transferrin whereas holo-Tf decreases the amount transported. The control condition is the basal media with no extra addition. B) Here, the data from panel A are shown as a percent of control. C) Apo-Tf in the basal chamber significantly increases the amount of iron transported by H-ferritin while holo-Tf decreases the amount transported relative to control. D) H-ferritin transport of iron from panel C as a percent of control conditions. All values are means ± SD, with statistical significance evaluated against the control (addition of Tf or Hft alone) using two-way ANOVA and Bonferroni’s post hoc comparisons. * = p<0.05, *** = p<0.001.
Table 1.
Transport of iron across the BBB.
Table 2.
Iron loading of endothelial cells.
Fig 3.
Schematic representation of hypothesized route of IV iron compound after administration.
After the IV iron formulations are administered, they are may be initially picked up by macrophages. The macrophages proceed to metabolize the IV iron formulations, storing the excess iron in H-ferritin (Hft). Additionally, free iron may be exported from the macrophage via ferroportin (FPN) where it may be picked up by circulating apo-transferrin or ferritin. Transferrin (Tf) or Hft can bind to transferrin receptor (TfR) or the T-cell immunoglobulin and mucin domain 1 (Tim-1) receptor [42], and then provide iron across the BBB as demonstrated in this study.