Modulation of innate immune exhaustion during sepsis

败血症期间先天免疫衰竭的调节

• 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
• 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

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.

项目摘要 实验性脓毒症中靶向选定促炎或抗炎介质的现有方法 大多数以失败告终，由于脓毒症患者经历的二分法的未解决的困境， 严重的免疫抑制以及加重的致病性炎症，共同导致 增加多器官损伤和对继发感染的免疫防御受损。我们的集成 结合scRNAseq分析的实验和计算研究扩展了我们对 在人类和动物中发现的传统定义的未成熟Ly 6Chi髓源性抑制细胞（MDSC） 脓毒症，因为这些低分化的Ly 6Chi单核细胞不仅是免疫抑制性的（具有升高的 免疫抑制因子PD-L1和免疫激活因子CD 86降低），而且还具有高致病性炎症（ 持续的ROS和升高的炎性介质S100 A8/9、CD 38和CX43），脓毒症的特征 来自患有实验性脓毒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， “耗尽的记忆单核细胞”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TLR 4衔接分子TRAM在细胞凋亡中起着关键作用。 耗竭单核细胞的产生，以及TRAM缺失可以减轻实验性脓毒症。基于 这些新的发现，我们的长期目标是确定新的治疗靶点，以减轻先天免疫 疲劳和预防/治疗败血症。作为关键的第一步，我们的主要目标是更好地描述 产生“记忆”耗尽的单核细胞和关键的潜在机制。我们计划测试中央 假设脓毒症发病过程中单核细胞耗竭记忆的产生是由 新的TRAM信号通路，靶向TRAM将在恢复单核细胞 体内平衡和预防/治疗严重脓毒症。为了检验这个假设，我们计划执行以下操作 综合研究。目标1。为了验证TRAM介导记忆产生的新表型假说， 单核细胞衰竭目标2.表征TRAM介导的新机制 产生耗尽的单核细胞。目标3.通过以下途径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和新颖的 负责产生单核细胞耗竭记忆导致脓毒症发病机制的机制， 并促进恢复单核细胞稳态的有效治疗策略的发展， 降低败血症死亡率/发病率。