Immunometabolism in Sepsis

 描述（由申请方提供）：脓毒症是一种发生在感染或损伤后患者中的临床全身炎症反应综合征，仍然是包括美国在内的全球重症监护病房的主要死亡原因。新的证据表明，免疫代谢可能通过其调节细胞因子的表达和释放的能力在脓毒症的发病机制中发挥重要作用。特别是，我们最近提供了第一个直接证据，证明PKM 2介导的有氧糖酵解促进HMGB 1的释放，HMGB 1是致命全身炎症的晚期介质，具有更宽的临床干预治疗时间窗。这些令人兴奋的发现提出了几个重要的问题，关于以前未知的PKM2在脓毒症发病机制中的作用，以及PKM2表达和HMGB1释放调节的新机制。我们假设PKM2介导的免疫代谢是脓毒症的一个新的标志，有助于细胞因子（例如，HMGB1）释放和随后的全身炎症反应。我们提出以下具体目标：目标1。定义脓毒症期间免疫和非免疫细胞中PKM2表达和活性调节的机制。我们将测试AMPK是PKM2表达和活性的负调节剂，因此在体外和体内抑制活化的巨噬细胞、单核细胞和内皮细胞中有氧糖酵解和HMGB1释放的假设。目标二。定义脓毒症期间免疫和非免疫细胞中有氧糖酵解调节HMGB1释放的机制。我们将检验代谢产物产生（例如，来自PKM2介导的有氧糖酵解的HMGB1（乳酸盐）可以抑制组蛋白脱乙酰酶（包括SIRT1）的活性，这反过来使得HMGB1能够在体外和体内在活化的巨噬细胞、单核细胞和内皮细胞中过度乙酰化并随后释放。目标3。在两种实验动物模型中确定PKM2抑制在预防脓毒症方面的功效。我们将检验这样的假设，即骨髓细胞中PKM2消融的小鼠通过改变乳酸积累、HMGB1释放、炎症反应和器官功能障碍而免受致死性内毒素血症或盲肠结扎和穿孔诱导的多微生物败血症的影响。这些令人兴奋的研究的完成将进一步提高我们对免疫代谢在炎症中的新作用和HMGB1释放机制的理解，并指导未来治疗败血症和其他致命炎症性疾病的治疗策略的发展。

 DESCRIPTION (provided by applicant): Sepsis, a clinical systemic inflammatory response syndrome occurring in patients following infection or injury, remains the leading cause of death in intensive care units worldwide, including the United States. Emerging evidence indicates that immunometabolism may play an important role in the pathogenesis of sepsis through its ability to regulate the expression and release of cytokines. In particular, we recently provided the first direct evidence that PKM2-mediated aerobic glycolysis promotes the release of HMGB1, a late mediator of lethal systemic inflammation with a wider therapeutic time window for clinical intervention. These exciting findings raise several important questions regarding the previously unknown role of PKM2 in the pathogenesis of sepsis, as well as the novel mechanisms underlying the regulation of PKM2 expression and HMGB1 release. We hypothesize that PKM2-mediated immunometabolism is an emerging hallmark of sepsis that contributes to cytokine (e.g., HMGB1) release and the subsequent systemic inflammatory response. We propose the following specific aims: Aim 1. Define the mechanism underlying the regulation of PKM2 expression and activity in both immune and non-immune cells during sepsis. We will test the hypothesis that AMPK is a negative regulator of PKM2 expression and activity, and therefore suppresses aerobic glycolysis and HMGB1 release in activated macrophages, monocytes, and endothelial cells in vitro and in vivo. Aim 2. Define the mechanism underlying the regulation of HMGB1 release by aerobic glycolysis in both immune and non-immune cells during sepsis. We will test the hypothesis that metabolites production (e.g., lactate) from PKM2-mediated aerobic glycolysis can inhibit the activity of histone deacetylases including SIRT1, which in turn enables HMGB1 hyperacetylation and subsequent release in activated macrophages, monocytes, and endothelial cells in vitro and in vivo. Aim 3. Determine the efficacy of PKM2 inhibition in protecting against sepsis in two experimental animal models. We will test the hypothesis that mice with PKM2 ablation in myeloid cells are protected from lethal endotoxemia or cecal ligation and puncture-induced polymicrobial sepsis through altering lactate accumulation, HMGB1 release, inflammatory response, and organ dysfunction. The completion of these exciting studies will further improve our understanding of the emerging role of immunometabolism in inflammation and the mechanisms of HMGB1 release and guide future development of therapeutic strategies to treat sepsis and other lethal inflammatory diseases.