Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammation

摘要 溶血伴随许多病理现象，包括创伤、败血症、出血性中风、疟疾和遗传性疾病。 镰状细胞病(SCD)和葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症等疾病。这个 游离的血红素释放到循环中促进了许多血管病变，因此，有效的血红素 清除和排毒是必要的，以防止持续的组织损伤。慢性溶血导致 由游离血红素引发的血管炎症，伴随着氧化组织损伤，这可能导致 氧化磷脂的产生与动脉粥样硬化和心脏代谢性疾病有关 并发症。在这里，我们将检验总体假设，即在溶血应激的情况下，G6PD缺乏 由于代谢适应功能障碍而变得越来越有害，而 巨噬细胞和单核细胞是解决SCD出血的关键。 在特定目标1中，我们将检验以下假设：巨噬细胞的代谢适应是有效的 血红素清除和细胞存活，并确定调节代谢转变的分子机制 在溶血的情况下的购买力平价。我们还将研究血红素解毒不足的后果。 对G6PD和Steap3转基因小鼠全身溶血中细胞存活和脂质氧化的影响 假设磷酸果糖激酶PBFKB3是CO激活PPP的靶标。在具体目标2中，我们 将证明代谢适应对SCD中的血红素解毒的重要性。我们将研究 SCD小鼠模型的代谢变化和SCD患者血液单核细胞代谢状态的特征。 这些研究将确定新的治疗靶点，以改善血红素的解毒和改善由血红素引起的 氧化组织损伤。

SUMMARY Hemolysis accompanies many pathologies including trauma, sepsis, hemorrhagic stroke, malaria, and genetic disorders such as sickle cell disease (SCD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. The release of free heme into the circulation promotes numerous vascular pathologies and therefore, efficient heme clearance and detoxification is necessary to prevent sustained tissue damage. Chronic hemolysis results in vascular inflammation driven by free heme, accompanied by oxidative tissue damage, which may lead to generation of oxidized phospholipids that are implicated in atherosclerosis and cardiometabolic disease complications. Here, we will test the overall hypothesis that in settings of hemolytic stress, G6PD deficiency becomes increasingly detrimental due to dysfunctional metabolic adaptation, and that metabolic adaptation of macrophages and monocytes is essential for the resolution of hemorrhage in SCD. In specific aim 1 we will test the hypothesis that metabolic adaptation in macrophages is necessary for efficient heme-clearance and cell survival and to determine the molecular mechanisms that regulate the metabolic shift to the PPP in the context of hemolysis. We will also examine the consequences of insufficient heme detoxification for cell survival and lipid oxidation in systemic hemolysis in G6PD and Steap3 transgenic mice and test the hypothesis that the phosphofructokinase PBFKB3 is the target for CO to activate the PPP. In specific aim 2 we will demonstrate the significance of metabolic adaptation to heme detoxification in SCD. We will examine metabolic shift in murine models of SCD and characterize blood monocyte metabolic state in SCD patients. These studies will identify novel therapeutic targets to improve heme detoxification and ameliorate heme-induced oxidative tissue damage.