BACKGROUND Atypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system. Multiple sclerosis is an immune-mediated neurological disease, and recently, clozapine was shown to reduce disease severity in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). However, the mode of action by which clozapine reduces disease in this model is poorly understood. METHODS Because the mode of action by which clozapine reduces neuroinflammation is poorly understood, we used the EAE model to elucidate the in vivo and in vitro effects of clozapine. RESULTS In this study, we report that clozapine treatment reduced the infiltration of peripheral immune cells into the central nervous system (CNS) and that this correlated with reduced expression of the chemokines CCL2 and CCL5 transcripts in the brain and spinal cord. We assessed to what extent immune cell populations were affected by clozapine treatment and we found that clozapine targets the expression of chemokines by macrophages and primary microglia. Furthermore, in addition to decreasing CNS infiltration by reducing chemokine expression, we found that clozapine directly inhibits chemokine-induced migration of immune cells. This direct target on the immune cells was not mediated by a change in receptor expression on the immune cell surface but by decreasing downstream signaling via these receptors leading to a reduced migration. CONCLUSIONS Taken together, our study indicates that clozapine protects against EAE by two different mechanisms; first, by reducing the chemoattractant proteins in the CNS; and second, by direct targeting the migration potential of peripheral immune cells.

中文翻译：

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氯氮平通过靶向在实验性自身免疫性脑脊髓炎中的迁移来减少对CNS的浸润。

背景技术非典型的抗精神病药，例如氯氮平，通过据信涉及调节免疫系统的机制用于治疗精神分裂症和其他精神疾病。多发性硬化症是一种免疫介导的神经系统疾病，最近，氯氮平被证明可降低MS动物模型（实验性自身免疫性脑脊髓炎（EAE））的疾病严重性。然而，在该模型中氯氮平减轻疾病的作用方式知之甚少。方法由于对氯氮平减少神经炎症的作用方式了解甚少，因此我们使用EAE模型阐明了氯氮平的体内和体外作用。结果在这项研究中，我们报道氯氮平治疗减少了周围免疫细胞向中枢神经系统（CNS）的浸润，并且这与趋化因子CCL2和CCL5转录物在脑和脊髓中的表达降低有关。我们评估了氯氮平治疗对免疫细胞群体的影响程度，并且我们发现氯氮平靶向巨噬细胞和原发性小胶质细胞趋化因子的表达。此外，除了通过减少趋化因子的表达减少中枢神经系统的浸润，我们发现氯氮平直接抑制趋化因子诱导的免疫细胞迁移。免疫细胞上的这种直接靶点不是由免疫细胞表面上受体表达的变化介导的，而是通过经由这些受体的下游信号传导的减少导致迁移减少而介导的。结论综合起来，我们的研究表明，氯氮平可通过两种不同的机制预防EAE；首先，通过减少中枢神经系统的趋化蛋白；其次，通过直接靶向外周免疫细胞的迁移潜力。