Age-related differences in neuroinflammatory responses associated with a distinct profile of regulatory markers on neonatal microglia.
BACKGROUND
The 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.


METHODS
In 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.


RESULTS
Of 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.


CONCLUSIONS
A 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.
Leah B
LB
Christensen
Tyson A
TA
Woods
Aaron B
AB
Carmody
Byron
B
Caughey
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, Canada. petersonka@niaid.nih.gov.
Karin E
KE
Peterson
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation; D040881:CD11a Antigen; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000633:toxicity; D011108:Polymers / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic; D013451:Sulfonic Acids / Q000633:toxicity; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D000943:Antigens, Differentiation; D040881:CD11a Antigen; C408982:CPG-oligonucleotide; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D011108:Polymers; C501922:Sirpa protein, mouse; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D013451:Sulfonic Acids; D051193:Toll-Like Receptors; C036763:monocyte-macrophage differentiation antigen; C077118:poly(2-acrylamido-2-methyl-1-propanesulfonic acid)