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-6Chigh 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 Deltaacta, but not Deltahly 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-6Chigh monocytes in Deltaacta-infected mice. Moreover, DeltaactA-infected IFN-gamma-/- mice had no brain influx of Ly-6Chigh 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.
Department of Medicine, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA. douglas-drevets@ouhsc.edu
Douglas A
DA
Drevets
Jennifer E
JE
Schawang
Marilyn J
MJ
Dillon
Megan R
MR
Lerner
Michael S
MS
Bronze
Daniel J
DJ
Brackett
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000276:immunology*; D002490:Central Nervous System / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D015854:Up-Regulation
D000950:Antigens, Ly; D007371:Interferon-gamma