Schematic illustration of the glucocorticoid effect on monocytes during extracellular Hb exposure. Native circulating blood monocytes have a moderate capacity to clear extracellular Hb. Glucocorticoids induce CD163 expression and stimulate receptor mediated Hb:Hp endocytosis. The resulting increase in intracellular heme leads to activation of the Nrf-2-Maf/MARE signaling pathway with subsequent enhancement of HO-1, ferroportin, and antioxidative genes (malic enzyme [ME]; NAD(P)H dehydrogenase quinone 1 [NQO1]; GCLM). Free iron that is released during HO-1–mediated heme degradation can activate the iron-regulated protein (IRP)/iron-responsive element (IRE) leading to increased synthesis of ferritin, suppression of the transferrin receptor (TfR), and increased expression of iron exporter ferroportin (Fpn).