Altered innate leukocyte programming dynamics in sepsis

败血症中先天白细胞编程动力学的改变

基本信息

批准号：
10292455
负责人：
LIWU LI
金额：
$ 40.25万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292455
关键词：
Animal Model Attenuated Back Biological Models CCR5 gene Chemicals Complex Data Development Dose Event FPR2 gene Gene Expression Genes Genetic Transcription Goals Harvest Health Homeostasis Host Defense Human Immune In Vitro Inflammation Inflammatory Inflammatory Response Intervention Knockout Mice Leukocytes Lipopolysaccharides Lysosomes Mediating Modeling Molecular Morbidity - disease rate Mus Nature Paralysed Pathogenesis Pathologic Phase Phosphoric Monoester Hydrolases Prevention Process Resolution Runaway Seminal Sepsis Sterility System Systems Analysis Testing Tissues base cecal ligation puncture chromatin remodeling dosage extracellular genetic approach in vivo in vivo Model migration monocyte mortality neutrophil novel novel strategies novel therapeutic intervention preconditioning programs promoter restoration septic septic patients tauroursodeoxycholic acid

项目摘要

PROJECT SUMMARY Sepsis poses grave health concerns with no effective prevention or cure. The key stumbling block is the highly complex nature of the disrupted innate leukocyte homeostasis. Disrupted sepsis monocyte homeostasis is reflected in a dramatic early upswing of inflammatory processes followed by a late-phase compensatory tolerance. Disrupted neutrophil homeostasis in sepsis patients is cardinally represented by “migratory paralysis” in which septic neutrophils lose migratory potential toward bacterial products while retaining migration toward sterile tissues, due to preferential reduction of FPR2 and induction of CCR5. Septic neutrophils also have reduced potential for generating neutrophil extra-cellular trap (NET). Collectively, these disrupted innate leukocyte homeostasis may compromise host defense and exacerbate multi-organ inflammation. However, mechanisms underlying monocyte priming and neutrophil paralysis are poorly understood. Due to their highly dynamic natures, current experimental systems in vitro or animal models in vivo fail to properly capture the disrupted leukocyte homeostasis. The PI’s past systems analyses with experimental and computational approaches reveal a model system that recapitulates the disrupted human leukocyte homeostasis in vitro and in vivo by applying subclinical super-low dose lipopolysaccharide (LPS). In sharp contrast to the effects of widely used higher dosages LPS which preferentially facilitate monocyte tolerance, Dr. Li’s lab documented that super- low dose LPS “primes” monocytes for prolonged “run-away” inflammation. In addition, Li lab observed that super- low dose LPS “programs” neutrophils into a paralytic state, mimicking septic neutrophils with reduced FPR2, reduced potential of bacterial killing and elevated CCR5. Monocyte priming and neutrophil paralysis by super- low dose LPS can be observed in human blood leukocyte ex vivo. With the cecal ligation and puncture sepsis model, Li lab demonstrated exacerbated sepsis mortality in mice pre-conditioned with super-low dose LPS. Mechanistically, Li lab observed that super-low dose LPS potently reprograms monocytes and neutrophils by disrupting key homeostatic events and molecules. Based on these intriguing observations, the long-term goal is to understand the disrupted innate immune dynamics responsible for the elevated morbidity and mortality of sepsis. As a crucial first step, our key objective is to better understand the mechanisms responsible for the disrupted homeostasis in monocytes and neutrophils. This project plans to test the central hypothesis that monocyte priming and neutrophil paralysis during sepsis are caused by the disruption of key homeostatic molecules and processes. Aim 1 will test the hypothesis that the disruption of homeostatic molecules such as RelB is responsible for the monocyte priming conducive for increased sepsis mortality. Aim 2 will reveal the fundamental cellular and molecular mechanisms responsible for neutrophil paralysis. Aim 3 will test whether that alteration of leukocyte dynamics may exacerbate, while restoration of leukocyte homeostasis may attenuate sepsis pathogenesis.

项目摘要败血症将严重的健康问题定位，没有有效的预防或治愈。关键的绊脚石是干扰的先天白细胞稳态的高度复杂性。败血症单核细胞稳态破坏反映在炎症过程的戏剧性早期上升，然后是后期补偿性宽容。败血症患者的中性粒细胞稳态破坏以“迁移瘫痪”为代表其中败血性嗜中性粒细胞失去对细菌产物的迁移潜力，同时将迁移迁移到无菌组织，由于首选降低FPR2和CCR5的诱导。化粪池中性粒细胞也有产生中性粒细胞外细胞陷阱（NET）的潜力降低。总的来说，这些干扰了先天的白细胞稳态可能会损害宿主防御和加剧多器官炎症。然而，单核细胞启动和中性粒细胞分析的机制知之甚少。由于他们的高度动态性质，当前体外实验系统或体内动物模型无法正确捕获白细胞稳态破坏。 PI过去的系统通过实验和计算进行分析方法揭示了一种模型系统，该系统概括了人类白细胞稳态的体外和通过施用亚临床超低剂量脂多糖（LPS）来体内。与广泛的影响形成鲜明对比利用较高剂量的LP，优先寄主单核细胞耐受性，Li博士的实验室记录了超级低剂量LPS“ Primes”单核细胞进行了长时间的“逃跑”注射。此外，Li Lab观察到超级低剂量LPS“程序”中性粒细胞进入瘫痪状态，模仿败血性嗜中性粒细胞，以降低的FPR2，细菌杀伤和CCR5升高的潜力降低。超级 - 单核细胞启动和中性粒细胞分析低剂量LP可以在人类白细胞外体内观察到。与盲肠结扎和穿刺败血症 Li Lab模型表明，用超低剂量LPS预先调节的小鼠中败血症的死亡率加剧。从机械上讲，Li Lab观察到超低剂量LPS可能会通过破坏关键的稳态事件和分子。基于这些有趣的观察，长期目标是为了了解造成升高的发病率和死亡率的干扰败血症。作为关键的第一步，我们的主要目标是更好地了解负责单核细胞和中性粒细胞中的稳态破坏。该项目计划检验中心假设败血症期间的单核细胞启动和中性粒细胞瘫痪是由关键稳态的破坏引起的分子和过程。 AIM 1将检验以下假设，即稳态分子的破坏，例如 RELB负责单核细胞启动导电剂增加败血症死亡率。 AIM 2将揭示基本的细胞和分子机制负责中性粒细胞瘫痪。 AIM 3将测试是否白细胞动力学的改变可能会加剧，而白细胞稳态的恢复可能会减弱败血症发病机理。