Zhao Xiurong, Sun Guanghua, Ting Shun-Ming, Song Shen, Zhang Jie, Edwards Nancy J, Aronowski Jaroslaw
Stroke Program - Department of Neurology, University of Texas Health Science Center, Medical School at Houston, Houston, Texas, USA.
J Neurochem. 2015 Apr;133(1):144-52. doi: 10.1111/jnc.12974. Epub 2014 Nov 24.
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.
由于脑出血（ICH），血液成分进入脑实质，对周围脑组织造成渐进性损伤。除非清除血肿，否则血液蓄积会继续对神经血管结构造成损伤，并阻碍脑修复过程。小胶质细胞/巨噬细胞（MMΦ）是介导血肿清除的主要吞噬系统。因此，MMΦ吞噬功能的有效性是限制ICH介导损伤的关键步骤。我们使用原代小胶质细胞模拟红细胞（血肿的主要成分）清除过程，研究了转录因子核因子红系2 p45相关因子2（Nrf2），一种抗氧化防御的主要调节因子，在血肿清除过程中的作用。我们发现，在培养的小胶质细胞中，Nrf2激活剂（i）诱导抗氧化防御成分，（ii）减少过氧化物形成，（iii）上调介导吞噬作用的清道夫受体CD36，以及（iv）增强红细胞（RBC）吞噬作用。通过DNA诱饵或中和抗体抑制小胶质细胞中的Nrf2或CD36，我们证明了Nrf2和CD36在RBC吞噬作用中的重要作用。使用自体血注射ICH模型测量血肿消退情况，我们发现，在ICH发作后给动物注射Nrf2激活剂萝卜硫素，可诱导ICH影响的大脑中CD36表达，并改善大鼠和野生型小鼠的血肿清除，但不出所料，在Nrf2基因敲除（KO）小鼠中则没有效果。Nrf2-KO小鼠的正常血肿清除受到损害。我们的实验表明，小胶质细胞中的Nrf2在增强ICH后的抗氧化能力、吞噬作用和血肿清除方面发挥重要作用。
