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: 7741731
• 负责人: JEFFREY A. GOLD
• 金额: $ 37.39万
• 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/7741731
• 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; DNA Binding; Data; Disease; Disease Marker; Gold; Human; Immune; Immune response; 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; adaptive immunity; 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.

败血症中的炎症主要由巨噬细胞激活程度控制。 cost刺激 分子是一类能够在适应性免疫中激活巨噬细胞的受体。连接 巨噬细胞通过CD154，CD28/CTLA4和LFA-1表达CD40，CD80/CD86和ICAM 细胞，增加NF-KB DNA结合以及C/EBPB的刺激/抑制同工型的比率。这导致 增加了许多炎症细胞因子的产生。但是，共刺激分子在 多数型败血症期间的先天免疫反应尚未得到很好的描述。我们最近描述了CD40- / - 小鼠的死亡率延迟，多数型败血症，NF-KB活性的衰减和比率 刺激/抑制性C/EBPB。现在，我们提供中性粒细胞的数据，这是先天免疫的主要组成部分 败血症的反应，可以通过摄取分子的参与直接激活巨噬细胞 在体外CD40，CD80/CD86和ICAM。在体内，与WT相比，CD80/CD86 - / - 小鼠的生存率提高了 CLP之后的小鼠。这与NF-KB的降低有关，刺激/抑制性C/EBPB和 BAL和血浆中IL-6和IL-10的水平。类似于自适应免疫的摩尔语中报道的内容， 对多种共刺激分子的抑制作用提供了额外的好处。 CD40/CD80/CD86 - / - 小鼠 与CD80/86 - / - 小鼠相比，CD80/CD86 - / - 小鼠中CD80/CD86 - / - 小鼠的ICAM中和。在 人类患有败血症，我们发现pmnexpersed CD28，CTLA4和CD154以及单核细胞的上调 与健康对照相比，表达CD40，CD80/CD86和ICAM。另外，可溶的同工型 与健康对照组相比，CD154，CD28，ICAM和CTLA4上调。 此外，SCD28和SCD154的水平仅在非幸存者中上调，这表明潜力 作为疾病活动的生物标志物的角色。这些结果共同表明了共刺激的重要作用 败血症中的分子。在此提案中，我们计划将这些观察结果扩展到：1。代表动力学 在鼠模型中，CD40-CD154，CD80/CD86-CD28/CTLA4和ICAM-LFA-1系统的活性 多数型败血症，2。测试败血症中多种共刺激分子抑制的作用 CD40/CD80/CD86 - / - 小鼠和3。 和活体内的活性和败血症和败血性休克的人体内的活体。