Immunometabolism in microbial sepsis

项目摘要/摘要 脓毒症是许多重症监护病房中最常见的死亡原因，其原因超过 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。败血症的特征是一种夸大的先天免疫反应，导致细胞因子风暴。 最近的研究表明，天然免疫细胞的激活会导致强烈的新陈代谢变化 提高葡萄糖利用率。糖代谢升高也是糖尿病初始状态的共同特征。 败血症。然而，糖代谢重编程在调节先天免疫功能中的作用 而它与脓毒症的相关性却知之甚少。在这项提案中，我们旨在研究两个人角色 微生物脓毒症中的葡萄糖代谢途径、氨基己糖生物合成途径(HBP)和 磷酸戊糖途径(PPP)。我们的初步研究揭示了HBP相关的O- O-Linkedβ-N-乙酰氨基葡萄糖信号转导与PPP在抗炎反应中的作用 细菌的传播。我们进一步确定核因子E2相关因子-2(Nrf2)是一种关键的 HBP和PPP通路的中介物。因此，促进HBP和PPP途径的活性 通过药理作用激活NRF2可能是一种很有前途的治疗方案 微生物败血症。我们推测：1)HBP相关的O-GlcNAc信号抑制先天免疫 通过O-GlcN酰化RIPK3(受体相互作用的丝氨酸/苏氨酸激酶3)激活；2)PPP是 脓毒症中巨噬细胞杀菌和宿主生存所必需的； 这些葡萄糖代谢途径的遗传和药物激活在治疗糖尿病中是有效的。 微生物败血症。将采用盲肠结扎和穿刺法诱导的多菌败血症模型 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到保护作用。该提案的目标是研究 两种糖代谢途径对巨噬细胞杀菌作用及机制的研究 炎症，两者都是宿主生存的关键决定因素。这些研究的结果将提供新的 对糖代谢信号的调节和功能的洞察，这可能会导致 寻找治疗微生物败血症的新靶点。

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.