Roles of microglia on the development of neurological disorders

本研究旨在通过对小胶质细胞功能的分析，探讨难治性神经系统疾病的发病机制。我们的研究结果总结如下：1）来自M-CSF缺陷op/op小鼠的小胶质细胞（II型小胶质细胞）不产生TNF、NO、IL-12 p70或IL-18，而来自野生型的小胶质细胞（主要是I型小胶质细胞）产生所有这些。这表明可能存在具有不同功能的不同亚型的小胶质细胞。由于小胶质细胞衍生的TNF或NO被认为在神经元变性或脱髓鞘的发展中起关键作用，因此两个小胶质细胞群体在上述病症的病理生理学中可能具有不同的作用。2）为了抑制小胶质细胞产生TNF或NO以用于未来的治疗，我们检测了磷酸二酯酶抑制剂（PDEI）对小胶质细胞产生TNF和NO的影响。PDEI抑制小胶质细胞产生TNF和NO，也抑制小鼠艾滋病病毒感染。PDEI还抑制了实验性过敏性脑脊髓炎（一种多发性硬化症的动物模型）的发展。不同类型的PDEI发挥协同作用。因此，2至3种不同的PDEI的组合疗法可用于将来治疗其中TNF或NO参与病理生理学的神经病症。3）IL-13与用于小胶质细胞增殖诱导的多核巨细胞（MGC）的其它刺激。MGC在结核病的HIV脑病或CNS受累中观察到。提示2型辅助性T细胞源性细胞因子可能参与了多核巨细胞的形成，研究小胶质细胞的功能及其修饰可能为治疗难治性神经系统疾病提供有用的信息。

The purpose of the study is to approach the mechanisms of intractable neurological disorders by analyzing the functions of microglia. The summary of our findings is as follows,1) Microglia derived from M-CSF deficient op/op mouse (type II microglia) did not produce either TNF, NO, IL-12 p70 or IL-18, while microglia derived from wild type (mainly type I microglia) produced all of them. This suggests that there may be different subtypes of microglia which have distinct functions. Since microglia-derived TNF or NO is considered to play critical roles on the development of neuronal degeneration or demyelination, two populations of microglia may have different roles on the pathophysiology of above conditions.2) In order to suppress TNF or NO production by microglia for future treatment, we examined the effects of phosphodiesterase inhibitors (PDEI) on TNF and NO production by microglia. PDEI suppressed TNF and NO production by microglia, also suppressed infection of murine AIDS virus in vitro. PDEI also suppressed the development of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Different types of PDEI functioned synergistically. Thus, the combination therapy of 2 to 3 different PDEI may be useful for future treatment of neurological disorders in which TNF or NO is involved in the pathophysiology.3) IL-13 with other stimulation for microglial proliferation induced multinucleated giant cell(MGC). MGC is observed in HIIV encephalopathy or CNS involvement of tuberculosis. The findings suggest the type 2 helper T cell-derived cytokines may be involved in the mechanisms of multinucleated giant cell formation.To study the function of microglia and its modification may provide us useful information for the strategy to treat intractable neurological disorders.