Biochemistry and Molecular Biology Unit, School of Medicine, University of Barcelona (UB, IDIBAPS), Barcelona, Spain.
Neurobiol Aging. 2012 Sep;33(9):2186-99. doi: 10.1016/j.neurobiolaging.2011.09.019. Epub 2011 Oct 19.
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.
神经炎症被认为在许多神经退行性疾病中发挥致病作用，包括肌萎缩侧索硬化症（ALS）。在这项研究中，我们证明了脂多糖（LPS）与干扰素-γ诱导的一氧化氮（NO）合酶-2（NOS2）和环氧化酶（COX）-2在 ALS 动物模型 G93A-SOD1 小鼠的小胶质细胞富集培养物中的表达高于野生型小鼠。CCAAT/增强子结合蛋白β（C/EBPβ）的水平也上调，C/EBPβ是一种调节促炎基因表达的转录因子，在激活的 G93A-SOD1 小胶质细胞中。在体内，全身脂多糖也会在 G93A-SOD1 小鼠中引起比野生型小鼠更严重的神经炎症反应，胶质纤维酸性蛋白（GFAP）、CD11b、NOS2、COX-2、促炎细胞因子和 C/EBPβ的表达增加。最后，我们报告 C/EBPβ在 ALS 患者的脊髓中由小胶质细胞表达。这是我们所知的人类疾病中小胶质细胞 C/EBPβ表达的首次证明。总之，这些发现表明 G93A-SOD1 的表达导致神经炎症加剧，并表明 C/EBPβ是调节 ALS 中小胶质细胞中潜在神经毒性基因表达的候选物。
