Modulation of innate immune exhaustion during sepsis

败血症期间先天免疫衰竭的调节

基本信息

批准号：
10680874
负责人：
LIWU LI
金额：
$ 54.38万
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：
2023
资助国家：
美国
起止时间：
2023-02-13 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680874
关键词：
Acute Animals Anti-Inflammatory Agents Attenuated CD86 gene Cell Maturation Characteristics Chronic Clustered Regularly Interspaced Short Palindromic Repeats Connexin 43 Development Exhibits Failure Generations Genetic Goals Homeostasis Human Immature Monocyte Immune Immunosuppression Immunosuppressive Agents Infection Inflammation Inflammation Mediators Inflammatory Intervention Mediating Mediator Memory Metabolic Morbidity - disease rate Mus Mycolic Acid Myelogenous Myeloid-derived suppressor cells NF-kappa B Natural Immunity Pathogenesis Pathogenicity Patients Phenotype Proto-Oncogene Proteins c-akt Reporting S100A8 gene STAT1 gene Sepsis Severities Signal Transduction TLR4 gene Testing Therapeutic computer studies exhaust exhaustion experience experimental study immune activator in vivo inflammatory marker monocyte mortality multiorgan injury new therapeutic target novel pharmacologic prevent programmed cell death ligand 1 secondary infection septic septic patients therapeutically effective tool translational potential

项目摘要

PROJECT SUMMARY Existing approaches targeting selected pro- or anti-inflammatory mediators during experimental sepsis mostly ended in failure, due to the un-resolved predicament of sepsis patients experiencing the dichotomy of severe immune-suppression as well as exacerbated pathogenic inflammation, collectively contributing to increased multi-organ injuries and compromised immune defense toward secondary infections. Our integrated experimental and computational studies combined with scRNAseq analyses expanded our understanding of the traditionally defined immature Ly6Chi myeloid derived suppressor cells (MDSCs) seen in human and animal sepsis, in that these less-differentiated Ly6Chi monocytes are not only immune suppressive (with elevated immune suppressor PD-L1 and reduced immune activator CD86), but also highly pathogenic inflammatory (with sustained ROS, and elevated inflammatory mediators S100A8/9, CD38 and CX43), characteristic of septic monocytes from human patients and animals with experimental sepsis. Instead of the traditional narrow definition of MDSC partially emphasizing their immune-suppressive features, we propose the holistic concept of “exhausted memory monocytes” encompassing both immune suppression and pathogenic inflammation. Mechanistically, we recently reported that the less-studied TLR4 adaptor molecule TRAM is critically involved in the generation of exhausted monocytes, and that TRAM deletion can alleviate experimental sepsis. Based on these novel findings, our long-term goal is to define novel therapeutic targets for relieving innate immune exhaustion and preventing/treating sepsis. As a crucial first step, our key objective is to better characterize the generation of “memory” exhausted monocytes and key underlying mechanisms. We plan to test the central hypothesis that the generation of monocyte exhaustion memory during sepsis pathogenesis are mediated by the novel TRAM signaling circuitry, and that targeting TRAM will hold a therapeutic potential in restoring monocyte homeostasis and preventing/treating severe sepsis. To test this hypothesis, we plan to perform the following integrated studies. Aim 1. To test the novel phenotypic hypothesis that TRAM mediates the generation of memory exhausted monocytes during sepsis. Aim 2. To characterize novel mechanisms underlying TRAM-mediated generation of exhausted monocytes. Aim 3. To examine the translational potential of sepsis intervention via reprogramming exhausted monocytes. Completion of this project will holistically reveal important and novel mechanisms responsible for the generation of monocyte exhaustion memory leading to sepsis pathogenesis, and facilitate the development of effective therapeutic strategies in restoring monocyte homeostasis and reducing sepsis mortality/morbidity.

项目概要针对实验性脓毒症期间选定的促炎或抗炎介质的现有方法由于脓毒症患者面临的二分法困境尚未解决，大多数以失败告终严重的免疫抑制以及加剧的致病性炎症，共同导致多器官损伤增加，对继发感染的免疫防御受损。实验和计算研究与 scRNAseq 分析相结合，扩展了我们对传统上定义的未成熟 Ly6Chi 骨髓源性抑制细胞 (MDSC) 在人类和动物中可见脓毒症，因为这些低分化的 Ly6Chi 单核细胞不仅具有免疫抑制作用（免疫抑制剂 PD-L1 和减少的免疫激活剂 CD86），而且还有高致病性炎症（持续的 ROS 和炎症介质 S100A8/9、CD38 和 CX43 升高），这是脓毒症的特征来自患有实验性败血症的人类患者和动物的单核细胞，而不是传统的狭义定义。 MDSC 部分强调其免疫抑制功能，我们提出了整体概念 “耗尽记忆单核细胞”包括免疫抑制和致病性炎症。从机制上讲，我们最近报道了研究较少的 TLR4 接头分子 TRAM 在耗尽的单核细胞的产生，以及 TRAM 删除可以减轻实验性脓毒症。这些新发现，我们的长期目标是确定缓解先天免疫的新治疗靶点疲劳和预防/治疗脓毒症作为关键的第一步，我们的主要目标是更好地描述脓毒症的特征。 “记忆”耗尽的单核细胞的产生和关键的潜在机制我们计划测试中央机制。假设脓毒症发病过程中单核细胞衰竭记忆的产生是由新颖的 TRAM 信号电路，并且靶向 TRAM 将具有恢复单核细胞的治疗潜力为了检验这一假设，我们计划执行以下操作。目的 1. 检验 TRAM 介导记忆生成的新表型假设。目标 2. 表征 TRAM 介导的新机制。目标 3. 通过以下方式检查脓毒症干预的转化潜力。重新编程耗尽的单核细胞该项目的完成将全面揭示重要且新颖的内容。负责产生单核细胞耗竭记忆导致脓毒症发病机制的机制，并促进制定有效的治疗策略来恢复单核细胞稳态和降低败血症死亡率/发病率。