Lipopolysaccharide differentially regulates microglial trk receptor and neurotrophin expression.
Activated brain microglia play a pivotal role in inflammatory and degenerative disorders, mediating immune function and producing toxic and trophic agents. We previously reported that microglia express neurotrophins and that neurotrophin-3 (NT-3) increases microglial proliferation and phagocytosis, processes associated with cellular activation. However, mechanisms regulating responsiveness to NT-3 and expression of NT-3 in activated microglia remain undefined. To investigate mechanisms governing microglial responsiveness to neurotrophins, we determined whether microglia express trk C, the high-affinity receptor for NT-3, and whether the inflammatory agent lipopolysaccharide (LPS) regulates receptor expression. Trk C mRNA was expressed by unstimulated microglia, and both trk C mRNA and protein were dramatically increased by LPS. In contrast, expression of trk A, the high-affinity receptor for nerve growth factor (NGF), was down-regulated by LPS. Consequently, the same stimulus differentially influences responsiveness of microglia to distinct trophins. In addition, LPS induced microglial NT-3 expression, suggesting that increases in both the ligand and receptor modulate NT-3 effects on microglia. Regulation was specific, since brain-derived neurotrophic factor (BDNF) and NT-4/5 expression were unaltered by LPS. In sum, our findings raise the possibility that microglial NT-3 regulates their response to inflammation through autocrine mechanisms: LPS modulates both trk C and NT-3 which, in turn, regulate microglial function.
Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert W. Johnson Medical School, Piscataway 08854, USA. elkabes@mbc1.rutgers.edu
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D015153:Blotting, Western; D001923:Brain Chemistry; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics*; D020933:Neurotrophin 3; D020033:Protein Isoforms / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D020917:Receptor, trkA / Q000032:analysis / Q000235:genetics*; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation
D008070:Lipopolysaccharides; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020033:Protein Isoforms; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC