Innate responses to systemic infection by intracellular bacteria trigger recruitment of Ly-6Chigh monocytes to the brain
Innate responses to systemic infection by intracellular bacteria trigger recruitment of Ly-6Chigh monocytes to the brain
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DOI：
10.4049/jimmunol.181.1.529
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Brackettt, Daniel J.
中科院分区：
文献类型：
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作者：
Drevets, Douglas A.;Schawang, Jennifer E.;Brackettt, Daniel J.
血液传播的单核细胞增生李斯特菌通过寄生的Ly-6C（高）单核细胞的迁移进入CNS，但触发这种迁移的信号尚不清楚。为了更全面地了解导致单核细胞募集的事件，本文提出的实验将实验感染小鼠脑中基因表达的微阵列分析与静脉内感染单核细胞增生李斯特菌后细菌CFU和血清细胞因子的测量相结合。在24和48小时感染后，大脑是无菌的，但有显着的变化，转录活性相关的血清促炎细胞因子。实时PCR证实了与IFN-γ、IL-1和TNF-α相关的基因的mRNA上调，尽管IFN-γ本身在大脑中没有上调。感染Delta acta，但不是Delta hly突变体，增加IFN-γ，IL-6的血清浓度，并在较小程度上TNF-α。大脑未被感染，但在Delta acta感染的小鼠中，大脑中存在广泛的mRNA上调和Ly-6C（高）单核细胞的流入。此外，尽管正常单核细胞从骨髓运输到血液和脾脏，但Δ actA感染的IFN-γ（-/-）小鼠没有Ly-6C（高）单核细胞的脑内流。此外，与正常小鼠相比，IFN-γ（-/-）小鼠显示单核细胞吸引趋化因子的mRNA表达减少，大脑中的CXCL 9和CXCL 10蛋白显著减少。这些数据表明，单核细胞向脑的募集不依赖于CNS的细菌入侵，并且由促炎性细胞因子（特别是IFN-γ）触发，所述促炎性细胞因子由对外周器官中的细胞内感染的先天免疫应答产生。
Blood borne Listeria monocytogenes enter the CNS via migration of parasitized Ly-6C(high) monocytes, but the signals that trigger this migration are not known. To understand more completely events leading to monocyte recruitment, experiments presented here combined microarray analysis of gene expression in the brains of experimentally infected mice with measurements of bacterial CFU and serum cytokines following i.v. infection with L monocytogenes. At 24 and 48 h postinfection, the brain was sterile but there were significant changes in transcriptional activity related to serum proinflammatory cytokines. Real-time PCR confirmed mRNA up-regulation of genes related to IFN-gamma, IL-1, and TNF-alpha, although IFN-gamma itself was not up-regulated in the brain. Infection with Delta acta, but not Delta hly mutants, increased serum concentrations of IFN-gamma, IL-6, and to a lesser extent TNF-alpha. The brain was not infected but there was widespread mRNA up-regulation in it and an influx of Ly-6C(high) monocytes in Delta acta-infected mice. Moreover, Delta actA-infected IFN-gamma(-/-) mice had no brain influx of Ly-6C(high) monocytes despite normal monocyte trafficking from bone marrow to blood and spleen. Additionally, IFN-gamma(-/-) mice showed diminished mRNA expression for monocyte-attracting chemokines, and significantly less CXCL9 and CXCL10 protein in the brain compared with normal mice. These data demonstrate that monocyte recruitment to the brain is independent of bacterial invasion of the CNS and is triggered by proinflammatory cytokines, in particular IFN-gamma, produced by the innate immune response to intracellular infection in peripheral organs.