Systemic stimulation of TLR2 impairs neonatal mouse brain development

• Published in: PloS one Vol. 6; no. 5; p. e19583
• Main Authors: Du, Xiaonan, Fleiss, Bobbi, Li, Hongfu, D'angelo, Barbara, Sun, Yanyan, Zhu, Changlian, Hagberg, Henrik, Levy, Ofer, Mallard, Carina, Wang, Xiaoyang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-05-2011; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; administration & dosage; Aging; Aging - drug effects; anatomy & histology; Animals; Animals, Newborn; Apoptosis; Apoptosis - drug effects; Bacteria; Biology; biosynthesis; Brain; Brain - drug effects; Brain - growth & development; Brain - immunology; Brain - pathology; Brain injuries; Brain injury; Brain research; Caspase; Caspase-3; Cell Proliferation; Cell Proliferation - drug effects; Cerebellum; Clinical Science; Cross infection; Cytokines; Cytokines - biosynthesis; deficiency; drug effects; Endotoxins; Fear conditioning; Forebrain; Gram-positive bacteria; growth & development; Head injuries; Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Hospitals; Hypoxia; Immune response; Immune system; immunology; Inbred C57BL; Inflammation; Inflammation - pathology; Injuries; Intensive care; Interleukin 6; Ischemia; Klinisk vetenskap; Laboratories; Learning; Learning - drug effects; Lipopeptides; Lipopeptides - administration & dosage; Lipopeptides - pharmacology; Lipopolysaccharides; Liver; Liver - anatomy & histology; Liver - drug effects; Long term memory; Long-term effects; Medicin och hälsovetenskap; Medicine; metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - pathology; Mitogens; Monocyte chemoattractant protein 1; Mycobacterium bovis; Neonates; Nervous system; Neurodegeneration; Neurons; Neurosciences; Newborn; Newborn babies; Newborn infants; Nosocomial infections; Organ Size; Organ Size - drug effects; pathology; Pediatrics; pharmacology; Physiology; Proteins; Receptors; Rehabilitation; Rodents; Sheep; Signaling; Spleen; Spleen - anatomy & histology; Spleen - drug effects; Staphylococcus epidermidis; Stimulation; Substantia alba; Substantia grisea; TLR2 protein; Toll-Like Receptor 2; Toll-Like Receptor 2 - deficiency; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Traumatic brain injury; Sweden; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019583

Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development.
Mice were injected intraperitoneally (i.p.) once a day from postnatal day (PND) 3 to PND11 with endotoxin-free saline, a TLR2 agonist Pam(3)CSK(4) (5 mg/kg) or Lipopolysaccharide (LPS, 0.3 mg/kg). Pups were sacrificed at PND12 or PND53 and brain, spleen and liver were collected and weighed. Brain sections were stained for brain injury markers. Long-term effects on memory function were assessed using the Trace Fear Conditioning test at PND50. After 9 days of Pam(3)CSK(4) administration, we found a decreased volume of cerebral gray matter, white matter in the forebrain and cerebellar molecular layer that was accompanied by an increase in spleen and liver weight at PND12. Such effects were not observed in Pam3CSK4-treated TLR 2-deficient mice. Pam3CSK4-treated mice also displayed decreased hippocampus neuronal density, and increased cerebral microglia density, while there was no effect on caspase-3 or general cell proliferation at PND12. Significantly elevated levels of IL-1β, IL-6, KC, and MCP-1 were detected after the first Pam3CSK4 injection in brain homogenates of PND3 mice. Pam(3)CSK(4) administration did not affect long-term memory function nor the volume of gray or white matter.
Repeated systemic exposure to the TLR2 agonist Pam(3)CSK(4) can have a short-term negative impact on the neonatal mouse brain.