Impact of Social Stress on TLR4-Induced Microbicidal Activity of CD11b+ Cells

描述（由申请人提供）：心理压力通常被认为是免疫抑制的，但现在已知在某些情况下压力可以增强免疫应答的某些方面。尽管有这些知识，相对较少的研究集中在应激诱导的免疫增强。因此，这项拨款提案的首要目标是确定压力如何增强对传染病的先天抵抗力。小鼠的社会压力源涉及身体互动，使其与其他类型的压力源不同。被称为社会破坏（SDR）的社会压力源具有改变群体生活小鼠的社会秩序和主导地位的额外特征。我们已经确定，这些相互作用增强了免疫反应的某些方面。例如，SDR导致CD 11b+骨髓细胞从骨髓运输至脾脏，在脾脏中，它们对皮质酮的抑制作用具有抗性，并且在用toll样受体（TLR）4激动剂脂多糖和脂质A体外刺激时产生显著更高水平的促炎细胞因子。SDR还增加脾CD 11b+巨噬细胞杀死培养物中大肠杆菌的能力。这种应激诱导的增强在体内也很明显;小鼠在感染E.大肠杆菌从血液和脾脏中清除细菌的速度比非应激对照组小鼠更快。由于通过TLR 4的信号传导严重影响巨噬细胞的杀微生物活性，并且由于SDR对CD 11b+细胞的作用依赖于TLR刺激，因此这是一个理想的模型系统，用于测试社会压力通过改变CD 11b+细胞上的TLR 4功能来增强对微生物感染的抵抗力的假设。制定了三个具体目标：1）使用杀微生物活性氧中间体（ROI）和一氧化氮（NO）作为结果变量，测试SDR是否增强脾CD 11b+细胞上的TLR 4表达和/或敏感性，2）检查这种增加的反应性是否依赖于促分裂原活化蛋白（MAP）激酶p38、JNK和ERK 1/2，3）检测SDR增强的TLR 4和MAP激酶信号传导对于清除细菌感染的重要性。这种跨学科的方法将提供有价值的洞察复杂的宿主-病原体的关系在静止和紧张时期。确定增强免疫功能的应激诱导的细胞变化可以刺激治疗传染病的新治疗方法。

DESCRIPTION (provided by applicant): Psychological stress is often thought to be immunosuppressive, but it is now known that in some cases stress can enhance certain aspects of the immune response. Despite this knowledge, relatively few studies have focused on stress-induced immunoenhancement. Therefore, the overarching goal of this grant proposal is to identify how stress enhances innate resistance to infectious disease. Social stressors in mice involve physical interactions, making them unique from other types of stressors. The social stressor called social disruption (SDR) has the added characteristic of changing social order and dominance in group-living mice. We have determined that these interactions enhance certain aspects of the immune response. For example, SDR results in the trafficking of CD11b+ myeloid cells from the bone marrow to the spleen, where they are resistant to the suppressive effects of corticosterone and produce significantly higher levels of pro-inflammatory cytokines upon in vitro stimulation with the toll-like receptor (TLR) 4 agonists lipopolysaccharide and lipid A. SDR also increases the capacity of splenic CD11b+ macrophages to kill Escherichia coli in culture. This stress-induced enhancement was also evident in vivo; mice exposed to SDR prior to infection with E. coli cleared the bacteria from the blood and spleen more rapidly than did non-stressed control mice. Because signaling through TLR4 heavily influences the microbicidal activities of macrophages, and because the effects of SDR on CD11b+ cells are dependent upon TLR stimulation, this is an ideal model system to test the hypothesis that social stress enhances resistance to microbial infection by altering TLR4 functioning on CD11b+ cells. Three specific aims have been developed to: 1) test whether SDR enhances TLR4 expression and/or sensitivity on splenic CD11b+ cells, using microbicidal reactive oxygen intermediates (ROI) and nitric oxide (NO) as outcome variables, 2) examine whether this increased reactivity is dependent upon mitogen activated protein (MAP) kinases p38, JNK, and ERK1/2, which can enhance microbicidal activity 3) examine the importance of SDR-enhanced TLR4 and MAP kinase signaling for clearing a bacterial infection. This interdisciplinary approach will provide valuable insight into the complex host-pathogen relationship during quiescent and stressful periods. Defining the stress-induced cellular changes that enhance immune functioning could stimulate new therapeutic approaches to treating infectious diseases.