As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, the reservoirs of blood continue to inflict injury to neurovascular structures and blunt the brain repair processes. Microglia/macrophages (MMΦ) represent the primary phagocytic system that mediates the cleanup of hematoma. Thus, the efficacy of phagocytic function by MMΦ is an essential step in limiting ICH‐mediated damage. Using primary microglia to model red blood cell (main component of hematoma) clearance, we studied the role of transcription factor nuclear factor‐erythroid 2 p45‐related factor 2 (Nrf2), a master‐regulator of antioxidative defense, in the hematoma clearance process. We showed that in cultured microglia, activators of Nrf2 (i) induce antioxidative defense components, (ii) reduce peroxide formation, (iii) up‐regulate phagocytosis‐mediating scavenger receptor CD36, and (iv) enhance red blood cells (RBC) phagocytosis. Through inhibiting Nrf2 or CD36 in microglia, by DNA decoy or neutralizing antibody, we documented the important role of Nrf2 and CD36 in RBC phagocytosis. Using autologous blood injection ICH model to measure hematoma resolution, we showed that Nrf2 activator, sulforaphane, injected to animals after the onset of ICH, induced CD36 expression in ICH‐affected brain and improved hematoma clearance in rats and wild‐type mice, but expectedly not in Nrf2 knockout (KO) mice. Normal hematoma clearance was impaired in Nrf2‐KO mice. Our experiments suggest that Nrf2 in microglia play an important role in augmenting the antioxidative capacity, phagocytosis, and hematoma clearance after ICH.

Microglia/Macrophages (MMφ) utilize the scavenger receptor CD36 to internalize the red blood cells (RBC) during the hematoma cleanup process after intracerebral hemorrhage (ICH). During RBC catabolism in phagosomes of MMφ, reactive oxygen species (ROS) are generated causing oxidative stress and injury to the phagocyte and the neurovascular unit. We propose that the treatment of MMφ with Nrf2 agonist (sulforaphane) could:(1) speed up the phagocytosis process by up‐regulating CD36 expression, and (2) improve MMΦ resistant to oxidative damage by up‐regulating the expression of antioxidative enzymes such as catalase (Cat) or superoxide dismutase‐1 (SOD).