Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval (CHUL) Research Center and Department of Anatomy and Physiology, Laval University, Laurier, Québec, Canada.
PLoS One. 2007 Mar 21;2(3):e310. doi: 10.1371/journal.pone.0000310.
Glucocorticoids are potent regulators of the innate immune response, and alteration in this inhibitory feedback has detrimental consequences for the neural tissue. This study profiled and investigated functionally candidate genes mediating this switch between cell survival and death during an acute inflammatory reaction subsequent to the absence of glucocorticoid signaling. Oligonucleotide microarray analysis revealed that following lipopolysaccharide (LPS) intracerebral administration at striatum level, more modulated genes presented transcription impairment than exacerbation upon glucocorticoid receptor blockage. Among impaired genes we identified ceruloplasmin (Cp), which plays a key role in iron metabolism and is implicated in a neurodegenative disease. Microglial and endothelial induction of Cp is a natural neuroprotective mechanism during inflammation, because Cp-deficient mice exhibited increased iron accumulation and demyelination when exposed to LPS and neurovascular reactivity to pneumococcal meningitis. This study has identified genes that can play a critical role in programming the innate immune response, helping to clarify the mechanisms leading to protection or damage during inflammatory conditions in the CNS.
糖皮质激素是先天免疫反应的有效调节剂，而这种抑制反馈的改变对神经组织有不利影响。本研究对在缺乏糖皮质激素信号后发生的急性炎症反应过程中，介导细胞存活和死亡之间这种转换的候选功能基因进行了分析和研究。寡核苷酸微阵列分析显示，在纹状体水平给予脂多糖 (LPS) 脑内给药后，阻断糖皮质激素受体时，转录受损的基因多于转录增强的基因。在受损基因中，我们鉴定出铜蓝蛋白 (Cp)，它在铁代谢中起关键作用，并与神经退行性疾病有关。Cp 是小胶质细胞和内皮细胞在炎症期间的天然神经保护机制，因为 Cp 缺陷小鼠在暴露于 LPS 时表现出铁积累和脱髓鞘增加以及对肺炎球菌性脑膜炎的神经血管反应性增加。本研究鉴定了在先天免疫反应编程中起关键作用的基因，有助于阐明中枢神经系统炎症条件下导致保护或损伤的机制。
