Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production
Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production
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DOI：
10.1128/iai.00714-12
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发表时间：
2012-10-01
影响因子：
3.1
通讯作者：
Bailey, Michael T.
中科院分区：
文献类型：
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作者：
Allen, Rebecca G.;Lafuse, William P.;Bailey, Michael T.
将小鼠暴露在一种名为社会干扰(SDR)的社会应激源中，包括在雄性间攻击期间反复的社会失败，会导致循环中细胞因子(如IL-1α和IL-1β)增加，并增加脾CD11b(+)巨噬细胞对炎症刺激的反应性。例如，在内毒素刺激下，暴露于应激源的小鼠巨噬细胞产生的细胞因子水平高于非应激对照的细胞。此外，SDR应激源通过Toll样受体4依赖的机制增强了这些巨噬细胞在体外和体内杀死大肠杆菌的能力。目前的研究验证了应激增强细菌杀灭是由于过氧亚硝酸盐的产生增加的假设。雄性小鼠暴露在SDR应激源下或不受干扰。在大肠杆菌的刺激下，暴露于SDR的小鼠的脾巨噬细胞表达诱导型一氧化氮合酶mRNA水平显著增加，并产生更高水平的过氧亚硝酸盐。阻断过氧亚硝酸盐的产生可消除SDR诱导的杀微生物活性的增加。在IL-1受体1型基因敲除小鼠中的研究表明，增加的杀菌活性和过氧亚硝酸根的产生依赖于IL-1信号。这些数据证实并扩展了IL-1信号对应激源诱导的免疫增强的重要性；抑制超氧化物或一氧化氮的产生既能抑制过氧亚硝酸盐的产生，又能抑制对大肠杆菌的杀灭，这一发现表明，过氧亚硝酸盐介导了应激源诱导的细菌杀灭增加。
Exposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1 alpha (IL-1 alpha) and IL-1 beta, and increased reactivity of splenic CD11b(+) macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to kill Escherichia coli both in vitro and in vivo, through a Toll-like receptor 4-dependent mechanism. The present study tested the hypothesis that stressor-enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation with E. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing of E. coli demonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing.