Decreased neuronal CD200 expression in IL-4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide.
Maintenance of the balance between pro- and anti-inflammatory cytokines in the brain, which is affected by the activation state of microglia, is important for maintenance of neuronal function. Evidence has suggested that IL-4 plays an important neuromodulatory role and has the ability to decrease lipopolysaccharide-induced microglial activation and the production of IL-1beta. We have also demonstrated that CD200-CD200R interaction is involved in immune homeostasis in the brain. Here, we investigated the anti-inflammatory role of IL-4 and, using in vitro and in vivo analysis, established that the effect of lipopolysaccharide was more profound in IL-4(-/-), compared with wildtype, mice. Intraperitoneal injection of lipopolysaccharide exerted a greater inhibitory effect on exploratory behaviour in IL-4(-/-), compared with wildtype, mice and this was associated with evidence of microglial activation. We demonstrate that the increase in microglial activation is inversely related to CD200 expression. Furthermore, CD200 was decreased in neurons prepared from IL-4(-/-) mice, whereas stimulation with IL-4 enhanced CD200 expression. Importantly, neurons prepared from wildtype, but not from IL-4(-/-), mice attenuated the lipopolysaccharide-induced increase in pro-inflammatory cytokine production by glia. These findings suggest that the neuromodulatory effect of IL-4, and in particular its capacity to maintain microglia in a quiescent state, may result from its ability to upregulate CD200 expression on neurons.
Lyons
Anthony
A
Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland. lyonsan@tcd.ie
McQuillan
Keith
K
Deighan
Brian F
BF
O'Reilly
Julie-Ann
JA
Downer
Eric J
EJ
Murphy
Aine C
AC
Watson
Melanie
M
Piazza
Alessia
A
O'Connell
Florence
F
Griffin
Rebecca
R
Mills
Kingston H G
KH
Lynch
Marina A
MA
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D055809:Illness Behavior; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; D016207:Cytokines; D008070:Lipopolysaccharides; D015847:Interleukin-4; C042739:antigens, CD200