Immunometabolism in microbial sepsis

项目总结/摘要 败血症是许多重症监护病房中最常见的死亡原因， 美国每年有25万人死亡。微生物感染和创伤是最常见的原因， 败血症脓毒症的特征在于过度的先天免疫应答，导致细胞因子风暴。 最近的研究表明，先天性免疫细胞的激活引起了剧烈的代谢变化， 增加葡萄糖利用率。葡萄糖代谢升高也是糖尿病初始状态下的常见特征。 败血症然而，葡萄糖代谢重编程在天然免疫功能调节中的作用 并且其与脓毒症的相关性知之甚少。在本建议中，我们旨在研究两个人的作用 微生物败血症中的葡萄糖代谢途径，己糖胺生物合成途径（HBP）和 戊糖磷酸途径（PPP）。我们的初步研究揭示了HBP相关的O- GlcNAc（O-连接的β-N-乙酰葡萄糖胺）信号传导和PPP在拮抗炎症反应和 细菌传播，分别。我们进一步确定了核因子E2相关因子2（Nrf2）作为一个关键的 HBP和PPP途径的介导剂。因此，促进HBP和PPP途径的活性 通过药理学激活Nrf2可能代表一种有前途的治疗方案， 微生物败血症我们假设1）HBP相关的O-GlcNAc信号转导抑制先天性免疫， 通过RIPK3（受体相互作用丝氨酸/苏氨酸激酶3）的O-GlcNAc酰化激活; 2）PPP是 通过介导半胱天冬酶-1活化，在脓毒症中为巨噬细胞细菌杀伤和宿主存活所需; 3） 这些葡萄糖代谢途径的遗传和药理学激活在治疗糖尿病中是有效的。 微生物败血症采用盲肠结扎和穿孔诱导的多微生物脓毒症模型， 葡萄糖代谢途径的作用和功能。我们将测试富马酸二甲酯（DMF） 治疗在脓毒症引起的死亡中起保护作用。该提案的目的是审查 两种葡萄糖代谢途径对巨噬细胞的杀菌作用及机制 炎症，两者都是宿主存活的关键决定因素。这些研究结果将提供新的 深入了解葡萄糖代谢信号的调节和功能，这可能会导致 鉴定治疗微生物脓毒症的新治疗靶点。

Project Summary/Abstract Sepsis is the most common cause of mortality in many intensive care units and is responsible for more than 250,000 deaths in the United States annually. Microbial infection and trauma are the most common causes of sepsis. Sepsis is characterized by an exaggerated innate immune response leading to a cytokine storm. Recent studies suggest that activation of the innate immune cells causes vigorous metabolic changes towards increased glucose utilization. Elevated glucose metabolism is also a common feature in the initial state of sepsis. However, the role of glucose metabolism reprogramming in the regulation of innate immune function and its relevance to sepsis is poorly understood. In this Proposal, we aim to study the role of two individual glucose metabolism pathways in microbial sepsis, the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Our preliminary studies revealed essential roles of HBP-associated O- GlcNAc (O-linked β-N-acetylglucosamine) signaling and PPP in antagonizing inflammatory response and bacterial spreading, respectively. We further identified nuclear factor E2-related factor-2 (Nrf2) as a critical mediator of both HBP and PPP pathways. Therefore, promoting the activities of HBP and PPP pathways through pharmacological activation of Nrf2 may represent a promising therapeutic regimen for treating microbial sepsis. We hypothesize that 1) HBP-associated O-GlcNAc signaling inhibits the innate immune activation through O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine kinase 3); 2) PPP is required for macrophage bacterial killing and host survival in sepsis by mediating caspase-1 activation; 3) Genetic and pharmacological activation of these glucose metabolism pathways is effective in the treatment of microbial sepsis. Cecal ligation and puncture-induced polymicrobial sepsis model will be employed to examine the role and functions of glucose metabolism pathways. We will test whether dimethyl fumarate (DMF) treatment plays a protective role in sepsis-induced mortality. The goal of the proposal is to examine the function and mechanism of two glucose metabolism pathways on macrophage bacterial killing and inflammation, both of which are key determinants of host survival. Results of these studies will provide novel insights into the regulation and function of glucose metabolism signaling, which can potentially lead to the identification of new therapeutic targets in the treatment of microbial sepsis.