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Innate Responses to Systemic Infection by Intracellular Bacteria Trigger Recruitment of Ly-6C^high Monocytes to the Brain¹

Douglas A. Drevets^2,*, Jennifer E. Schawang^*, Marilyn J. Dillon^*, Megan R. Lerner, Michael S. Bronze^* and Daniel J. Brackett

^* Department of Medicine and Department of Surgery, Oklahoma University Health Sciences Center and the Veterans Affairs Medical Center, Oklahoma City, OK 73104

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-, IL-1, and TNF-, although IFN- itself was not up-regulated in the brain. Infection with acta, but not hly mutants, increased serum concentrations of IFN-, IL-6, and to a lesser extent TNF-. The brain was not infected but there was widespread mRNA up-regulation in it and an influx of Ly-6C^high monocytes in acta-infected mice. Moreover, actA-infected IFN-^–/– mice had no brain influx of Ly-6C^high monocytes despite normal monocyte trafficking from bone marrow to blood and spleen. Additionally, IFN-^–/– 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-, produced by the innate immune response to intracellular infection in peripheral organs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by grants from the Department of Veterans Affairs and the University of Oklahoma College Of Medicine Alumni Association (to D.A.D.).

² Address correspondence and reprint requests to Dr. Douglas A. Drevets, Veterans Affairs Medical Center 111/C, 921 Northeast 13th Street, Oklahoma City, OK 73104. E-mail address: douglas-drevets{at}ouhsc.edu

³ Abbreviations used in this paper: PI, postinfection; HPRT, hypoxanthine phosphoribosyl transferase; qPCR, real-time PCR.

⁴ The online version of this article contains supplemental material.