Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage
Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage
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DOI：
10.1016/s0306-4522(02)00144-6
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发表时间：
2002-01-01
期刊：
影响因子：
3.3
通讯作者：
Ling, EA
中科院分区：
文献类型：
--
作者：
Hao, AJ;Dheen, ST;Ling, EA
产前暴露于致畸剂与神经发育障碍的发病机制有关，但导致神经发育障碍的机制尚不清楚。为了阐明这一点，我们建立了一个由神经元损伤引起的小胶质细胞激活的体外模型。在这方面，原代小胶质细胞暴露于条件培养基中，从致畸原，环磷酰胺诱导的神经元损伤。通过逆转录聚合酶链反应、酶联免疫吸附试验、凝集素组织化学、双标记免疫组织化学和原位杂交评估，伴有反应性小胶质细胞增生。我们的研究结果表明，反应性小胶质细胞能够释放多种细胞因子，如肿瘤坏死因子- α、白细胞介素-1、白细胞介素-6、转化生长因子- β和一氧化氮。此外，我们已经证明巨噬细胞集落刺激因子（M-CSF）实际上是由反应性小胶质细胞产生的。与此同时，在致畸原诱导的神经元损伤后，这些细胞中M-CSF受体的表达增加。M-CSF受体的上调表明细胞能够以自分泌的方式对自源的M-CSF作出反应。抗体中和的结果进一步表明，以细胞因子表达为表现的小胶质细胞促炎反应是由M-CSF介导的，M-CSF作为启动小胶质细胞反应的分子信号。因此，我们认为环磷酰胺治疗后的小胶质细胞激活不仅是对神经元损伤的反应，也是神经发育障碍发病过程中损伤的原因之一。因此，M-CSF及其受体在小胶质细胞上表达的增加可能与致畸源诱导损伤中细胞增殖活跃和促炎反应直接相关。(c) 2002年ibro。Elsevier Science Ltd.出版。版权所有。
Prenatal exposure to teratogen agents is linked to the pathogenesis of neurodevelopment disorders, but the mechanisms leading to the neurodevelopmental disturbance are poorly understood. To elucidate this, an in vitro model of microglial activation induced by neuronal injury has been characterized. In this connection, exposure of primary microglial cells to the conditioned medium from the neuronal damage induced by teratogen, cyclophosphamide. is accompanied by a reactive microgliosis as assessed by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, lectin histochemistry, double labeling immunohistochemistry and in situ hybridization. Our results showed that reactive microglia were capable of releasing various cytokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, transforming growth factor-beta and nitric oxide. Also, we have shown that macrophage colony-stimulating factor (M-CSF) was in fact produced by the reactive microglia. Concomitant to this was the increased expression of M-CSF receptor in these cells following the teratogen-induced neuronal injury. The up-regulation of M-CSF receptor suggests that the cells are capable of responding to self-derived M-CSF in an autocrine fashion. Results with antibody neutralization further suggest that microglial proinflammatory response, as manifested by cytokine expression in culture, is mediated by M-CSF, which acts as a molecular signal that initiates a microglial reaction. We therefore suggest that microglial activation following cyclophosphamide treatment is not only a response to the neuronal damage, but is also a cause of the damage during pathogenesis of neurodevelopment disorders. To this end, the increased expression of M-CSF and its receptor on microglia would be directly linked to the active cell proliferation and proinflammatory response in the teratogen-induced injury. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.