Neuroprotective role of microglia expressing interleukin-4.
Little is known about the underlying mechanisms responsible for the death of activated microglia and the functional consequences of the death of these cells, especially in vivo. We show here that intracortical injection of lipopolysaccharide (LPS) led to upregulation of interleukin-4 (IL-4) immunoreactivity, followed by a substantial loss of microglia 3 days later, as visualized by complement receptor type 3 (OX-42) immunostaining and tomato lectin staining. Cells positive for caspase-3 and terminal deoxynucleotidyl transferase mediated fluorescein-dUTP nick-end labeling (TUNEL) were also localized within LPS-activated microglia. IL-4 immunoreactivity was detected as early as 12 hr post-LPS, disappearing at 72 hr. Surprisingly, IL-4 immunoreactivity was detected exclusively in microglia, but not in astrocytes or neurons. In addition, IL-4-neutralizing antibodies markedly increased the survival of activated microglia at 3 days post-LPS. The expression of inducible nitric oxide synthase (iNOS) and tumor-necrosis factor (TNF)-alpha was sustained in parallel in activated microglia, consequently increasing neuronal cell death. To our knowledge, this study is the first to show the endogenous expression of IL-4 in LPS-activated microglia in vivo. Our findings suggest that IL-4 may regulate brain inflammation by inducing the death of activated microglia in vivo and increasing neuronal survival.
Park
K W
KW
Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Lee
D Y
DY
Joe
E H
EH
Kim
S U
SU
Jin
B K
BK
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D004347:Drug Interactions; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D015847:Interleukin-4 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D039481:CD11b Antigen; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D037121:Plant Lectins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C034981:tomato lectin; D015847:Interleukin-4; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010751:Phosphopyruvate Hydratase