C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis.
Neuroinflammation is thought to play a pathogenic role in many neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). In this study we demonstrate that the expression of nitric oxide (NO) synthase-2 (NOS2), and cyclooxygenase (COX)-2 induced by lipopolysaccharide (LPS) with interferon-γ is higher in microglial-enriched cultures from G93A-SOD1 mice, an ALS animal model, than from wild type mice. The levels of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor that regulates proinflammatory gene expression, are also upregulated in activated G93A-SOD1 microglial cells. In vivo, systemic lipopolysaccharide also induces an exacerbated neuroinflammatory response in G93A-SOD1 mice versus wild type mice, with increased expression of glial fibrillary acidic protein (GFAP), CD11b, nitric oxide synthase-2, cyclooxygenase-2, proinflammatory cytokines, and C/EBPβ. Finally, we report that C/EBPβ is expressed by microglia in the spinal cord of ALS patients. This is the first demonstration to our knowledge of microglial C/EBPβ expression in human disease. Altogether these findings indicate that G93A-SOD1 expression results in an exacerbated pattern of neuroinflammation and suggest that C/EBPβ is a candidate to regulate the expression of potentially neurotoxic genes in microglial cells in ALS.
Biochemistry and Molecular Biology Unit, School of Medicine, University of Barcelona (UB, IDIBAPS), Barcelona, Spain.
Tony
T
Valente
Pilar
P
Mancera
Josep M
JM
Tusell
Joan
J
Serratosa
Josep
J
Saura
D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016759:Oncogene Protein p65(gag-jun) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D016759:Oncogene Protein p65(gag-jun); D012333:RNA, Messenger; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase