Figure 7. Proposed model to explain perivascular iron deposition inside microglia/macrophages in marmoset EAE lesions.

Iron accumulates inside microglia/macrophages, which show increased expression of transferrin receptor (TfR), a main iron influx protein. Iron itself is transported across the endothelium of nearby blood vessels, which also upregulates TfR. Increased levels of hepcidin (HpC), which binds, internalizes, and degrades ferroportin (FpN), the main iron efflux channel protein, also contributes to intracellular iron accumulation. Iron regulation returns to homeostasis in remyelinated lesions, though iron levels within these cells remain high. Demyelinated lesions continue to show both dysregulated iron metabolism and persistent iron deposition. The source of iron observed in the oligodendrocyte-lineage cells of remyelinated lesions is not addressed by this study, but possible mechanisms include both direct transendothelial transport and release from microglia/macrophages.