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，但现在知道，在某些情况下，压力可以增强免疫反应的某些方面。尽管有这些知识，相对较少的研究集中在压力诱导的免疫增强。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。老鼠的社会压力源包括身体上的相互作用，这使得它们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居小鼠社会秩序和支配地位的附加特征。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CD11b+骨髓细胞从骨髓转运到脾脏，在那里它们抵抗皮质酮的抑制作用，并在体外受到toll样受体（TLR） 4激动剂脂多糖和脂质a的刺激时产生显著更高水平的促炎细胞因子。SDR还增加了脾CD11b+巨噬细胞杀死培养的大肠杆菌的能力。这种应力诱导的增强在体内也很明显；在感染大肠杆菌之前暴露于SDR的小鼠比没有应激的对照组小鼠更快地清除了血液和脾脏中的细菌。由于通过TLR4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CD11b+细胞的作用依赖于TLR的刺激，因此这是一个理想的模型系统，可以测试社会压力通过改变TLR4对CD11b+细胞的功能来增强对微生物感染的抵抗。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是否增强了TLR4在脾CD11b+细胞上的表达和/或敏感性；2)检查这种增加的反应性是否依赖于有丝分裂原活化蛋白（MAP）激酶p38、JNK和ERK1/2，它们可以增强杀微生物活性；3)检查SDR增强的TLR4和MAP激酶信号对于清除细菌感染的重要性。这种跨学科的方法将提供宝贵的见解，复杂的宿主-病原体关系在静止和紧张时期。确定应激诱导的细胞变化，增强免疫功能，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.