Model illustrating how Nrf2 activation via the deletion of Keap1 in ECs or monocytes/granulocytes contributes individually to ameliorating the SCD phenotype. In SCD, chronic hemolysis alters the balance between the production and detoxification of antioxidants. In macrophages, for instance (left), Nrf2 insufficiency impairs the safe storage and metabolism of iron ions and free heme. Upon Nrf2 overexpression, macrophages can break down and store free heme and iron in less toxic molecules and decrease the production of oxidative species. In ECs (right), hemolysis and lower levels of Nrf2 promote the activation of ECs, expression of adhesion molecules, and impairment of endothelial barrier integrity (orange board). Activation of Nrf2 (green panel) inhibits the expression of Vcam1 and P-selectin, upregulates the expression of antioxidant enzymes, and, last but not least, inhibits vascular leakage by restoring the integrity of the vascular endothelium. EC-specific or monocyte/granulocyte-specific activation of Nrf2 ultimately protects organs from inflammation and damage in a distinct manner.