Role of Macrophage Costimulatory 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: 7211817
• 负责人: JEFFREY A. GOLD
• 金额: $ 38.44万
• 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/7211817
• 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

DESCRIPTION (provided by applicant): 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 PMN expressed 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 compared to 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

描述（由申请人提供）：脓毒症中的炎症主要由巨噬细胞活化程度控制。共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。通过激活的 T 细胞上的 CD154、CD28/CTLA4 和 LFA-1 连接表达 CD40、CD80/CD86 和 ICAM 的巨噬细胞，增加 NF-kB DNA 结合以及 C/EBPb 刺激/抑制亚型的比率。这导致大量炎症细胞因子的产生增加。然而，共刺激分子在多种微生物败血症期间先天免疫反应中的作用尚未得到很好的描述。我们最近描述了 CD40-/- 小鼠因多种微生物败血症而延迟死亡，其中 NF-kB 活性和刺激性/抑制性 C/EBPb 比率减弱。我们现在提供的数据表明，中性粒细胞是脓毒症先天免疫反应的主要组成部分，可以在体外通过共刺激分子 CD40、CD80/CD86 和 ICAM 的参与直接激活巨噬细胞。在体内，CLP 后，与 WT 小鼠相比，CD80/CD86-/- 小鼠的存活率有所提高。这与 BAL 和血浆中 NF-kB、刺激性/抑制性 C/EBPb 比率以及 IL-6 和 IL-10 水平的降低有关。与适应性免疫模型中报道的类似，抑制多种共刺激分子提供了额外的益处。与 CD80/86-/- 小鼠相比，CLP 后 CD40/CD80/CD86-/- 小鼠和 CD80/CD86-/- 小鼠中的 ICAM 中和均提高了存活率。在脓毒症患者中，与健康对照相比，我们发现 PMN 表达 CD28、CTLA4 和 CD154，单核细胞表达 CD40、CD80/CD86 和 ICAM 上调。此外，与健康对照相比，脓毒症患者中 CD154、CD28、ICAM 和 CTLA4 的可溶性同工型上调。此外，sCD28 和 sCD154 的水平仅在非幸存者中上调，表明其作为疾病活动生物标志物的潜在作用。总之，这些结果表明共刺激分子在脓毒症中发挥着重要作用。在本提案中，我们计划将这些观察扩展到：1.在多种微生物败血症的小鼠模型中表征CD40-CD154、CD80/CD86-CD28/CTLA4和ICAM-LFA-1系统的动力学和活性，2.通过新型CD40/CD80/CD86-/-测试败血症中多种共刺激分子的抑制效果 小鼠，以及 3. 全面评估脓毒症和感染性休克患者体内和离体共刺激分子表达和活性的重要性