Mitochondrial Biogenesis is Regulated by RelB During Inflammation

描述(由申请人提供)：本提案的目标是确定线粒体代谢和生物能量学的改变如何影响脓毒症的免疫抑制阶段。脓毒症的发病率正在上升，目前还没有特效的治疗方法，大多数死亡发生在过度炎症后的免疫抑制阶段。我们利用脓毒症和人类脓毒症血白细胞的细胞模型发现，NAD+依赖的脱乙酰酶Sirt1(Sirt1)激活了NF-kB因子RelB，将前炎症转换为免疫抑制，减少了葡萄糖依赖的合成代谢途径，增加了分解代谢脂解和线粒体脂肪酸氧化。我们还发现Sirt1激活的RelB诱导线粒体调节因子SIRT3的表达，作为线粒体蛋白，SIRT3促进分解代谢脂肪酸氧化和线粒体呼吸。此外，RelB还转位到线粒体，结合线粒体启动子DNA，增加线粒体基因的转录。值得注意的是，当在免疫抑制阶段给予Sirt1抑制时，显著提高了脓毒症小鼠的存活率。大量数据支持，从合成代谢到分解代谢的转换会损害葡萄糖依赖的效应者的免疫反应。基于这些集体数据：这一建议将检验这样的假设，即长期的Sirt1激活通过Sirt1-RelB-SIRT3核-线粒体轴(这里称为Sirt1轴)减少髓系来源的天然免疫细胞中的净合成代谢和增加净分解代谢，从而对脓毒症的预后产生不利影响。我们设计了3个目标来探索这一新概念：目标1：确定在脓毒症免疫抑制过程中，Sirt1轴的激活是否改变了线粒体代谢和生物能量学。目的：探讨Sirt1轴在脓毒症免疫抑制阶段对线粒体基因表达和电子传输链的调控作用。目的3：确定Sirt1和RelB如何调节SIRT3的表达。方法：将使用最先进的生化、分子细胞生物学和遗传学工具来研究基于细胞、小鼠和人类的脓毒症反应。影响：完成这些目标将确定Sirt1轴在脓毒症免疫抑制先天免疫中的作用，识别由Sirt1轴控制的精确线粒体和核过程，并引入一种通过重新平衡免疫代谢轴的净功能来治疗疾病的新方法。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine how alterations in mitochondrial metabolism and bioenergetics influence the immunosuppressive phase of sepsis. Sepsis incidence is rising, there are no specific therapies, and most deaths occur during the phase of immunosuppression that follows hyperinflammation. We discovered using a cell-based model of sepsis and human sepsis blood leukocytes that NAD+-dependent deacetylase Sirtuin 1 (Sirt1) activates NF-kB factor RelB to switch proinflammation to immunosuppression, reduce glucose-dependent anabolic pathways and increase catabolic lipolysis and mitochondrial fatty acid oxidation. We also find that Sirt1-activated RelB induces expression of mitochondrial regulator Sirt3, which as a mitochondrial protein promotes catabolic fatty acid oxidation and mitochondrial respiration. Moreover, RelB translocates to mitochondria, binds mitochondrial promoter DNA, and increases transcription of mitochondrial genes. Remarkably, Sirt1 inhibition markedly improves survival of septic mice when administered during the immunosuppressive phase. Substantial data support that switching from anabolism to catabolism can compromise glucose-dependent effector immune responses. Based on these collective data: This proposal will test the hypothesis that protracted Sirt1 activation adversely affects sepsis outcome through a Sirt1-RelB-Sirt3 nuclear-mitochondrial axis (here, called the Sirt1 axis) to decrease net anabolic and increase net catabolic metabolism in myeloid-derived innate immune cells. We have designed 3 aims to explore this new concept: Aim 1: Determine whether Sirt1 axis activation alters mitochondrial metabolism and bioenergetics during sepsis immunosuppression. Aim 2: Determine how mitochondrial gene expression and the electron transport chain are regulated by the Sirt1 axis during the immunosuppressed phase of sepsis. Aim 3: Define how Sirt1 and RelB regulate Sirt3 expression. Approach: Cell-based, murine and human sepsis responses will be investigated using state-of-the art biochemical, molecular cell biology, and genetics tools. Impact: Completing these aims will define the role of the Sirt1 axis in sepsis immunosuppression of innate immunity, identify precise mitochondrial and nuclear processes controlled by the Sirt1 axis, and introduce a new way to treat the disease by rebalancing the net function of the immunometabolic axis.