Figure 3.

Nrf2/HO-1 counteracts heme toxicity. In sickle cell disease, erythrocytes are deformed by the polymerization of hemoglobin S, and oxidative stress subsequently develops, inducing intravascular hemolysis and vaso-occlusion. An increase in the free heme concentration activates Nrf2 and induces HO-1 expression. HO-1 degrades heme into biliverdin, which is subsequently reduced into the antioxidant bilirubin. Nrf2 activation increases fetal hemoglobin levels by inducing the expression of the γ-globin gene and alleviates hemoglobin S production in erythroid progenitor cells. Nrf2 activation attenuates damage to multiple tissues, as well as the production of inflammatory cytokines.