Genes Involved in the Balance between Neuronal Survival and Death during Inflammation

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（glucocorticoids）是先天免疫应答的强效调节因子，该抑制性反馈通路的异常会对神经组织造成有害影响。本研究针对糖皮质激素信号缺失后急性炎症反应中，介导细胞存活与死亡之间转换的功能性候选基因开展了表达谱分析与功能研究。寡核苷酸微阵列分析显示，向纹状体区域脑内给予脂多糖（lipopolysaccharide, LPS）后，相较于糖皮质激素受体阻断后出现的基因表达增强，受调控的基因中更多呈现转录功能受损。在上述转录受损的基因中，我们鉴定出铜蓝蛋白（ceruloplasmin, Cp）：其在铁代谢中发挥关键作用，且与神经退行性疾病密切相关。炎症过程中，小胶质细胞与内皮细胞对铜蓝蛋白的诱导表达是一种天然神经保护机制——铜蓝蛋白缺陷小鼠在暴露于脂多糖后，会出现铁蓄积增加与脱髓鞘现象，且其对肺炎球菌性脑膜炎的神经血管反应性发生改变。本研究鉴定出可在调控先天免疫应答中发挥关键作用的基因，有助于阐明中枢神经系统（central nervous system, CNS）炎症状态下引发保护或损伤的潜在机制。