Abstract
BackgroundThe perinatal period is one in which the mammalian brain is particularly vulnerable to immune-mediated damage. Early inflammation in the central nervous system (CNS) is linked with long-term impairment in learning and behavior, necessitating a better understanding of mediators of neuroinflammation. We therefore directly examined how age affected neuroinflammatory responses to pathogenic stimuli.MethodsIn mice, susceptibility to neurological damage changes dramatically during the first few weeks of life. Accordingly, we compared neuroinflammatory responses to pathogen associated molecular patterns (PAMPs) of neonatal (two day-old) and weanling (21 day-old) mice. Mice were inoculated intracerebrally with PAMPs and the cellular and molecular changes in the neuroinflammatory response were examined.ResultsOf the 12 cytokines detected in the CNS following toll-like receptor 4 (TLR4) stimulation, ten were significantly higher in neonates compared with weanling mice. A similar pattern of increased cytokines in neonates was also observed with TLR9 stimulation. Analysis of cellular responses indicated a difference in microglial activation markers in the CNS of neonatal mice and increased expression of proteins known to modulate cellular activation including CD11a, F4/80 and CD172a. We also identified a new marker on microglia, SLAMF7, which was expressed at higher levels in neonates compared with weanlings.ConclusionsA unique neuroinflammatory profile, including higher expression of several proinflammatory cytokines and differential expression of microglial markers, was observed in brain tissue from neonates following TLR stimulation. This increased neuroinflammatory response to PAMPs may explain why the developing brain is particularly sensitive to infection and why infection or stress during this time can lead to long-term damage in the CNS.
Highlights
The perinatal period is one in which the mammalian brain is vulnerable to immune-mediated damage
Neuroinflammatory responses are increased in neonates compared with weanling mice To determine if the neuroinflammatory response changes in the first weeks of life, we inoculated neonatal and weanling (21 day-old) mice ic with either the toll-like receptor 4 (TLR4) agonist, LPS, or the TLR9 agonist, unmethylated CpG oligodeoxynucleotides (CpG-ODN)
The levels of several cytokines induced by TLR4 and/or TLR9 ligand induction were significantly higher in neonates than those observed in weanlings
Summary
The perinatal period is one in which the mammalian brain is vulnerable to immune-mediated damage. The mammalian brain is developing rapidly and is sensitive to inflammation or maternal stress. Current research suggests that it may not be the infectious agent per se but the immune response that is causing the neurological damage [2,7,8]. Neonatal rodent models have demonstrated that perinatal immune stimulation with either infectious agents or Toll-like receptor (TLR) ligands can produce developmental and behavioral changes similar to those observed in human neurological illnesses, including alterations in learning and memory [8,11]. Understanding the immune response in the CNS during the perinatal period is necessary in order to understand how developmental abnormalities and neurological damage may occur
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