Role of Macrophage Costimualtory Molecules in Polymicrobial Sepsis

巨噬细胞共刺激分子在多种微生物脓毒症中的作用

• 批准号: 7339019
• 负责人: JEFFREY A. GOLD
• 金额: $ 37.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339019
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological; Biological Markers; CD14 gene; CD28 gene; CD40 Antigens; CD80 gene; CTLA4 gene; Cells; Cellular Immunity; Class; DNA Binding; Data; Disease; Disease Marker; Gold; Human; Immune; Immune response; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Investigation; Kinetics; Knockout Mice; Ligands; Ligation; Macrophage Activation; Mediating; Modeling; Molecular Profiling; Mononuclear; Mus; NF-kappa B; Natural Immunity; Outcome; Pathway interactions; Patients; Phase; Plasma; Play; Production; Protein Isoforms; Puncture procedure; Regulation; Reporting; Research Personnel; Role; Sepsis; Septic Shock; Severities; Survivors; System; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; Testing; Up-Regulation; attenuation; chemokine; cytokine; improved; in vivo; intercellular cell adhesion molecule; macrophage; monocyte; mortality; neutrophil; novel; pathogen; programs; receptor; septic

Inflammation in sepsis is controlled primarily by the degree of macrophage activation. Costimulatory molecules are a class of receptors capable of macrophage activation in adaptive immunity. Ligation of macrophage expressed CD40, CD80/CD86 and ICAM by CD154, CD28/CTLA4 and LFA-1 on activated T- cells, increases NF-kB DNA binding and the ratio of stimulatory/inhibitory isoforms of C/EBPb. This results in increased production of numerous inflammatory cytokines. However, the role for costimulatory molecules in the innate immune response during polymicrobial sepsis is not well described. We recently described CD40- /- mice have delayed mortality with polymicrobial sepsis with attenuations in NF-kB activity and the ratio of stimulatory/inhibitory C/EBPb. We now present data that neutrophils, a main component of innate immune response in sepsis, can directly activate macrophages via engagement of the costimulatory molecules CD40, CD80/CD86 and ICAM in vitro. In vivo, CD80/CD86-/- mice have improved survival compared to WT mice after CLP. This was associated with a reduction in NF-kB, the ratio of stimulatory/inhibitory C/EBPb and levels of IL-6 and IL-10 in BAL and plasma. Similar to what has been reported in moels of adaptive immunity, inhibtion for multiple costimulatory molecules provided additional benefit. Both CD40/CD80/CD86-/- mice and ICAM neutralization in CD80/CD86-/- mice improved survival compared to CD80/86-/- mice after CLP. In humans with sepsis, we found upregulation of PMNexpressed CD28, CTLA4 and CD154, and monocyte expressed CD40, CD80/CD86 and ICAM compared to healthy controls. In addition, the soluble isoforms of CD154, CD28, ICAM and CTLA4 were upregulated in septic patients comparedto healthy controls. Furthermore, levels of sCD28 and sCD154 were only upregulated in non-survivors, suggesting a potential role as a biomarker of disease activity. Together, these results suggest an important role for costimulatory molecules in sepsis. In this proposal we plan to extend these observations to: 1. Characterize the kinetics and activity of the CD40-CD154, CD80/CD86-CD28/CTLA4 and ICAM-LFA-1 systems in a murine model of polymicrobial sepsis, 2. Test the effect of inhibition of multiple costimulatory molecules in sepsis via a novel CD40/CD80/CD86-/- mouse, and 3. To fully assess the significance of costimulatory molecule expression and activity both in vivo and ex vivo in humans with sepsis and septic shock.

脓毒症的炎症主要由巨噬细胞的激活程度控制。共刺激作用 在适应性免疫中，分子是一类能够激活巨噬细胞的受体。结扎术 巨噬细胞表面CD154、CD28/CTLA4和LFA-1表达CD40、CD80/CD86和ICAM 细胞，增加核因子-kB DNA结合和C/EBPB刺激/抑制亚型的比率。这将导致 大量炎性细胞因子的产生增加。然而，共刺激分子在 多菌败血症时的先天免疫反应尚未得到很好的描述。我们最近描述了CD40- /-多菌败血症小鼠的死亡率随着核因子-kB活性的降低和 刺激性/抑制性C/EBPB。我们现在提供的数据表明，中性粒细胞是先天免疫的主要组成部分 在脓毒症中的反应，可以通过参与共刺激分子直接激活巨噬细胞 CD40、CD80/CD86和ICAM。在体内，与WT相比，CD80/CD86-/-小鼠的存活率有所提高 CLP后小鼠。这与核因子-kB、刺激/抑制C/EBPB和 BAL和血浆中IL-6和IL-10的水平。类似于在适应性免疫的Moels中所报道的， 抑制多个共刺激分子提供了额外的好处。CD40/CD80/CD86-/-小鼠 与CD80/86-/-小鼠相比，CD80/CD86-/-小鼠的ICAM中和可提高CLP后的存活率。在……里面 脓毒症患者外周血单个核细胞CD28、CTLA4、CD154及单核细胞表达上调 CD40、CD80/CD86和ICAM的表达与健康对照组比较。此外，可溶性的异构体 脓毒症患者CD154、CD28、ICAM和CTLA4表达上调。 此外，sCD28和sCD154的水平仅在死亡患者中上调，这表明 作为疾病活动性的生物标志物。综上所述，这些结果表明了协同刺激的重要作用。 败血症中的分子。在这项建议中，我们计划将这些观察扩展到：1.表征动力学 CD40-CD154、CD80/CD86-CD28/CTLA4和ICAM-LFA-1系统的活性 多菌败血症，2.通过一种新的方法测试多个共刺激分子在脓毒症中的抑制效果 CD40/CD80/CD86-/-小鼠，以及3.充分评估共刺激分子表达的意义 以及患有败血症和感染性休克的人类体内和体外的活性。