Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway
Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway
复制标题
DOI：
10.1152/ajpregu.00307.2007
复制
发表时间：
2007-09-01
影响因子：
2.8
通讯作者：
Sheridan, John F.
中科院分区：
文献类型：
--
作者：
Bailey, Michael T.;Engler, Harald;Sheridan, John F.
先天免疫系统的吞噬细胞，如单核细胞/巨噬细胞，代表了抵抗入侵微生物的第一道防线。心理压力通常被认为会抑制这些细胞的功能，部分原因是压力诱导的糖皮质激素的免疫抑制活性。然而，暴露于应激源社会破坏（SDR）已被证明会增加单核细胞/巨噬细胞的细胞因子产生，并降低其对皮质酮的敏感性。因此，假设来自社会应激小鼠的脾单核细胞/巨噬细胞将被引发为比来自非应激对照的细胞更具生理活性。流式细胞术用于证明暴露于SDR显著增加脾巨噬细胞表面上的Toll样受体（TLR）2和4的表达。在后续实验中，暴露于SDR也增加了这些巨噬细胞体外和体内杀死大肠杆菌的能力。然而，SDR未能增加C3 H/ HeJ小鼠脾巨噬细胞的杀菌活性，其缺乏功能性TLR 4。在具有功能性TLR 4的小鼠中，应激诱导的杀菌活性的增加与诱导型一氧化氮合酶和NADPH氧化酶复合物亚基的巨噬细胞基因表达的显著增加相关，所述诱导型一氧化氮合酶和NADPH氧化酶复合物亚基分别负责产生活性氮和氧中间体。这种应激诱导的基因表达增加在TLR 4缺陷小鼠中并不明显。这些数据表明，SDR增加TLR表达，这反过来又增强脾巨噬细胞的杀菌活性，部分是通过增加负责活性氧和氮中间产物产生的途径。
Phagocytes of the innate immune system, such as monocytes/ macrophages, represent a first line of defense against invading microorganisms. Psychological stress is often thought to suppress the functioning of these cells, in part due to the immunosuppressive activity of stressinduced glucocorticoid hormones. However, exposure to the stressor social disruption ( SDR) has been shown to increase cytokine production by monocytes/ macrophages and to reduce their sensitivity to corticosterone. Thus, it was hypothesized that splenic monocytes/ macrophages from socially stressed mice would be primed to be more physiologically active than cells from nonstressed controls. Flow cytometry was used to demonstrate that exposure to SDR significantly increased the expression of Toll- like receptors ( TLR) 2 and 4 on the surface of splenic macrophages. In a follow- up experiment, exposure to SDR also increased the ability of these macrophages to kill Escherichia coli ex vivo and in vivo. However, SDR failed to increase the bactericidal activity of splenic macrophages from C3H/ HeJ mice, which lack functional TLR4. In mice with functional TLR4, the stress- induced increase in bactericidal activity was associated with a significant increase in macrophage gene expression for inducible nitric oxide synthase and subunits of the NADPH oxidase complex, which are responsible for generating reactive nitrogen and oxygen intermediates, respectively. This stress- induced increase in gene expression was not evident in the TLR4- deficient mice. These data indicate that SDR increases TLR expression, which in turn enhances the bactericidal activity of splenic macrophages, in part by increasing pathways responsible for reactive oxygen and nitrogen intermediate production.