title: TLR2-mediated leukocyte trafficking to the developing brain.
abstract: Inflammation is a significant risk factor for brain injury in the perinatal period. In this study, we tested the hypothesis that activation of peripheral TLR induces inflammation in the brain, including leukocyte trafficking. Postnatal day 8 mice were injected intraperitoneally with a TLR1/2 (Pam3CSK4, P3C), TLR2/6 (FSL-1) or TLR4 (LPS) agonist, and the peripheral and central cytokine and chemokine response was determined. Infiltration of immune cells to the CSF and brain was examined by flow cytometry, and brain permeability was investigated by radioactively labeled sucrose. We report that peripheral administration of P3C to neonatal mice induces significant influx of leukocytes, mainly neutrophils and monocytes, to the CSF and brain. Infiltration of leukocytes was TLR2 and MyD88 dependent, but largely absent after administration of LPS or FSL-1. PC3-mediated accumulation of immune cells in the brain was observed in classic CNS-leukocyte gateways, the subarachnoid space and choroid plexus, as well as in the median eminence. Although P3C and LPS induced a similar degree of peripheral inflammatory responses, P3C provoked a distinct brain chemokine response and increased permeability, in particular, of the blood-CSF barrier. Collectively, our results do not support the hypothesis that TLR activation, in general, induces immune cell infiltration to the brain. Instead, we have discovered a specific TLR2-mediated mechanism of CNS inflammation and leukocyte invasion into the neonatal brain. This interaction between peripheral and central immune responses is to a large extent via the blood-CSF barrier.
authors: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Amin
authors: A
authors: Mottahedin
authors: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Peter Lawrence Phillip
authors: PL
authors: Smith
authors: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom; and.|Perinatal Center, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Henrik
authors: H
authors: Hagberg
authors: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: C Joakim
authors: CJ
authors: Ek
authors: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; carina.mallard@neuro.gu.se.
authors: Carina
authors: C
authors: Mallard
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002555:Cerebrospinal Fluid / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D013395:Sucrose / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000819:agonists / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D016207:Cytokines; D055666:Lipopeptides; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C508075:Pam(3)CSK(4) peptide; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D013395:Sucrose
keywords: BBB; BCSFB; PAM3CSK4; inflammation; meningitis; pleocytosis