Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University, 60590 Frankfurt, Germany.
Free Radic Biol Med. 2011 May 15;50(10):1382-91. doi: 10.1016/j.freeradbiomed.2011.02.036. Epub 2011 Mar 5.
Inflammatory conditions and oxidative stress contribute to the development of atherosclerosis. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective properties. Its role in effecting a deactivated state of oxidized low-density lipoprotein (oxLDL)-generated foam cell macrophages (FCMs), a prevailing cellular phenotype of atherosclerotic lesions, has not been investigated yet. In this study RAW264.7- or mouse peritoneal macrophage-derived FCMs showed reduced mRNA expression of proinflammatory cytokines such as IL-1β and IL-6 and an attenuated production of reactive oxygen species (ROS), as analyzed by hydroethidine in response to lipopolysaccharide (LPS) and compared to LPS-treated control macrophages. In peritoneal FCMs from Nrf2-/- mice (C57BL/6J), the LPS-induced proinflammatory response was restored. OxLDL induced heme oxygenase (HO)-1, which was Nrf2-dependent, and inhibition of HO-1 activity in FCMs using zinc protoporphyrin-IX allowed the cells to regain a proinflammatory phenotype. Mechanistically, oxLDL attenuated ROS-dependent activation of CCAAT/enhancer binding protein (C/EBP) family members in FCMs, thereby reducing cytokine expression. Thus, in FCMs the Nrf2/HO-1 axis intervenes in LPS signaling. ROS production is impaired, C/EBP transactivation is reduced, and consequently the expression of proinflammatory mediators is attenuated, thereby shaping a desensitized FCM phenotype. This macrophage phenotype may be important for the progression of atherosclerosis.
炎症状态和氧化应激是动脉粥样硬化发生发展的重要因素。核因子 E2 相关因子 2（Nrf2）是一种氧化还原敏感的转录因子，具有抗氧化、抗炎作用，从而起到保护细胞的作用。但其在氧化型低密度脂蛋白（oxLDL）诱导的泡沫细胞巨噬细胞（FCM）中发挥作用的机制仍不清楚，oxLDL 诱导的泡沫细胞巨噬细胞是动脉粥样硬化病变的主要细胞表型。在本研究中，RAW264.7 或小鼠腹腔巨噬细胞衍生的 FCM 显示，与 LPS 处理的对照组巨噬细胞相比，促炎细胞因子（如 IL-1β 和 IL-6）的 mRNA 表达减少，脂多糖（LPS）刺激后活性氧（ROS）的产生减少，用羟乙基噻唑二唑蓝（hydroethidine）进行分析。在 Nrf2-/- 小鼠（C57BL/6J）的腹腔 FCM 中，LPS 诱导的促炎反应得到恢复。oxLDL 诱导血红素加氧酶（HO-1），这一过程依赖于 Nrf2，而用锌原卟啉 IX 抑制 FCM 中的 HO-1 活性，使细胞恢复促炎表型。从机制上讲，oxLDL 减弱了 FCM 中 ROS 依赖性 CCAAT/增强子结合蛋白（C/EBP）家族成员的激活，从而减少了细胞因子的表达。因此，在 FCM 中，Nrf2/HO-1 轴干预 LPS 信号。ROS 产生受损，C/EBP 反式激活减少，促炎介质的表达减弱，从而形成一种脱敏的 FCM 表型。这种巨噬细胞表型可能对动脉粥样硬化的进展很重要。
