Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development
Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development
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DOI：
10.1093/brain/awr032
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发表时间：
2011-04-01
期刊：
影响因子：
14.5
通讯作者：
Aronica, Eleonora
中科院分区：
文献类型：
--
作者：
Zurolo, Emanuele;Iyer, Anand;Aronica, Eleonora
最近在癫痫发作和颞叶癫痫的实验模型中的证据支持高迁移率族蛋白1和Toll样受体4信号传导在导致癫痫发作发展和持续的过度兴奋机制中的重要作用。在这项研究中，我们调查的表达和细胞分布的Toll样受体2和4，晚期糖基化终产物的受体，其内源性配体高迁移率族蛋白1，在癫痫与局灶性畸形的皮质发育。免疫组化显示局灶性皮质发育不良、结节性硬化症患者的皮质结节和神经节细胞胶质瘤中反应性胶质细胞中Toll样受体2和4以及晚期糖基化终产物受体表达增加。Toll样受体2主要在小胶质细胞/巨噬细胞谱系的细胞中检测到，在局灶性皮质发育不良的球囊细胞中检测到，在结节性硬化症复合体中检测到巨细胞。Toll样受体4和晚期糖基化终产物受体在星形胶质细胞和发育不良的神经元中表达。实时定量聚合酶链反应证实了所有病理系列中受体信使RNA水平的增加。在对照皮质标本中未检测到这些受体。在对照组皮层，高迁移率族蛋白1普遍存在于神经胶质细胞和神经元细胞的核中。在病理学标本中，蛋白质染色，而不是检测到在细胞质中的反应性星形胶质细胞或肿瘤星形胶质细胞，以及在活化的小胶质细胞，预测其从神经胶质细胞的释放。体外培养的人星形胶质细胞实验表明，白细胞介素-1 β可诱导高迁移率族蛋白B1的核质易位。我们的研究结果提供了新的证据，这些促炎信号通路的内在激活局灶性畸形的皮质发育，这可能有助于这些发展病变的高致癫痫性。
Recent evidence in experimental models of seizures and in temporal lobe epilepsy support an important role of high-mobility group box 1 and toll-like receptor 4 signalling in the mechanisms of hyperexcitability leading to the development and perpetuation of seizures. In this study, we investigated the expression and cellular distribution of toll-like receptors 2 and 4, and of the receptor for advanced glycation end products, and their endogenous ligand high-mobility group box 1, in epilepsy associated with focal malformations of cortical development. Immunohistochemistry showed increased expression of toll-like receptors 2 and 4 and receptor for advanced glycation end products in reactive glial cells in focal cortical dysplasia, cortical tubers from patients with the tuberous sclerosis complex and in gangliogliomas. Toll-like receptor 2 was predominantly detected in cells of the microglia/macrophage lineage and in balloon cells in focal cortical dysplasia, and giant cells in tuberous sclerosis complex. The toll-like receptor 4 and receptor for advanced glycation end products were expressed in astrocytes, as well as in dysplastic neurons. Real-time quantitative polymerase chain reaction confirmed the increased receptors messenger RNA level in all pathological series. These receptors were not detected in control cortex specimens. In control cortex, high-mobility group box 1 was ubiquitously detected in nuclei of glial and neuronal cells. In pathological specimens, protein staining was instead detected in the cytoplasm of reactive astrocytes or in tumour astrocytes, as well as in activated microglia, predictive of its release from glial cells. In vitro experiments in human astrocyte cultures showed that nuclear to cytoplasmic translocation of high-mobility group box 1 was induced by interleukin-1 beta. Our findings provide novel evidence of intrinsic activation of these pro-inflammatory signalling pathways in focal malformations of cortical development, which could contribute to the high epileptogenicity of these developmental lesions.