Department of Medical Biochemistry and.
Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan; and.
Blood Adv. 2019 Apr 23;3(8):1285-1297. doi: 10.1182/bloodadvances.2018017574.
Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower α and β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.
镰状细胞病（SCD）是由β-珠蛋白基因突变引起的，影响着全球数百万人。SCD 与持续的溶血性贫血、血管阻塞、缺血再灌注损伤、氧化组织损伤、炎症细胞激活和全身内皮功能障碍有关。转录因子 Nrf2 协调着编码抗氧化剂、解毒剂和代谢酶的多种基因的表达。Nrf2 参与抑制 SCD 中的促炎细胞因子和器官保护。然而，对于 Nrf2 改善 SCD 病理的机制以及某些细胞如何响应 Nrf2 刺激来减轻 SCD 病理，我们知之甚少。在这里，我们想知道单核细胞/粒细胞和/或内皮细胞是否在缓解 SCD 病理方面特别重要。通过用 Cre 重组酶系统靶向这些细胞，我们分别在单核细胞/粒细胞和内皮细胞中生成了 SCD::Keap1F/F::LysM-Cre 和 Tie1-Cre 小鼠，这些细胞中 Nrf2 持续激活。对 SCD::Keap1F/F::LysM-Cre 和 SCD::Keap1F/F::Tie1-Cre 小鼠的分析表明，炎症明显减轻，白细胞计数降低，肺部的 α 和 β 表达降低。值得注意的是，SCD::Keap1F/F::LysM-Cre 小鼠的肝脏中血红素分布减少，与受损区域减少相一致。SCD::Keap1F/F::Tie1-Cre 小鼠的血管功能显著改善，血管渗漏减少了 50%，粘附分子 Vcam1 和 P-选择素的表达降低。因此，单核细胞/粒细胞和内皮细胞中 Nrf2 的激活以不同的方式共同促进 SCD 病理的改善。
