Glucocorticoids play a fundamental role in protecting the brain during innate immune response
Glucocorticoids play a fundamental role in protecting the brain during innate immune response
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DOI：
10.1523/jneurosci.23-13-05536.2003
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发表时间：
2003-07-02
影响因子：
5.3
通讯作者：
Rivest, S
中科院分区：
文献类型：
--
作者：
Nadeau, S;Rivest, S
先天免疫系统在保护宿主免受传染性微生物侵害方面发挥着至关重要的作用。由于特定促炎分子的持续产生，对该系统的不当控制可能会产生深远的后果。糖皮质激素是最有效的内源性分子，可为促炎信号传导和基因表达提供负反馈。在这里，我们证明该系统的激活对大脑无害，但在接受糖皮质激素受体抑制剂米非司酮（RU486）治疗的动物中会发生严重的神经变性。这种药物会增加单次脑内推注脂多糖（LPS）引起的炎症反应。肿瘤坏死因子α（TNF-α）的抑制完全消除了内毒素的神经毒性作用，细胞因子的长期输注模拟了RU486和LPS的联合治疗。 TNF-α 引起的神经元损伤依赖于一氧化氮和半胱天冬酶途径。在控制大脑先天免疫和小胶质细胞 TNF-α 的产生方面，糖皮质激素在保护大脑免受细菌细胞壁成分的侵害方面发挥着重要作用。
The innate immune system plays a crucial role in protecting the host against infectious microorganisms. An inappropriate control of this system may have profound consequences, because of the maintained production of specific proinflammatory molecules. Glucocorticoids are the most efficient endogenous molecules that provide negative feedback on proinflammatory signaling and gene expression. Here we show that activation of this system is not detrimental for the brain but a profound neurodegeneration takes place in animals treated with the glucocorticoid receptor inhibitor Mifepristone (RU486). This drug increased the inflammatory reaction induced by a single intracerebral bolus of lipopolysaccharide (LPS). Inhibition of tumor necrosis factor alpha (TNF-alpha) totally abolished the neurotoxic effect of the endotoxin, and chronic infusion of the cytokine mimicked the treatment combining RU486 and LPS. The neuronal damage caused by TNF-alpha is dependent on both nitric oxide and caspase pathways. In controlling the cerebral innate immunity and microglial TNF-alpha production, glucocorticoids play a major role in protecting the brain against bacterial cell wall components.