Innate responses to systemic infection by intracellular bacteria trigger recruitment of Ly-6Chigh monocytes to the brain

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.