The role of microglia on the development of neurological disorders

本研究旨在探讨小胶质细胞功能的调控机制，以阐明炎症性神经系统疾病的病理生理机制，并寻找新的治疗策略。在中枢神经系统中，小胶质细胞作为抗原呈递细胞和炎性细胞起作用以诱导自身免疫性疾病，如多发性硬化症。我们已经发现小胶质细胞产生调节T辅助细胞分化的IL-12家族细胞因子（Suzumura等人，2003年，Sonobe等人，2005年）。小胶质细胞的一个亚群，称为2型小胶质细胞，不产生IL-12家族细胞因子。对于MS的治疗，在日本只有干扰素-β可用。我们已经表明，干扰素-β增强小胶质细胞的炎症功能，这可能与包括不适、发热等的副作用的发展有关。磷酸二酯酶抑制剂，如异丁司特，有效地抑制干扰素-b的促炎作用，表明干扰素和磷酸二酯酶抑制剂的组合疗法用于治疗MS的可能作用（Kawanokuchi等人，2004，Feng等人，2004年）。腺苷酸环化酶激活多肽（PACAP）和自由基清除剂依达拉朋也抑制小胶质细胞的促炎功能并改善实验性自身免疫性脑脊髓炎的临床评分（Kato等人，2004年，Banno等人，2005).小胶质细胞被认为在诱导轴突损伤中起关键作用。我们已经发现小胶质细胞通过分泌谷氨酸来干扰神经元的能量产生。因此，通过激活的小胶质细胞抑制谷氨酸的产生可能是未来治疗MS患者的策略。

In this study we focused to investigation of regulatory mechanisms of microglial functions to clarify the pathophysiology of inflammatory neurological disorders and to search new therapeutic strategies. In the central nervous system, microglia function as antigen presenting cells, and inflammatory cells to induce autoimmune diseases such as multiple sclerosis. We have found the microglia produce IL-12 family cytokines which regulate differentiation of T helper cells (Suzumura et al., 2003,Sonobe et al., 2005). One subpopulation of microglia, designated as type 2 microglia do not prouduce IL-12 family cytokines. For the treatment of MS, only interferon-β is available in JAPAN. We have shown that interferon-β enhances inflammatory functions of microglia which may related to the development of adverse effects including malaise, fever etc. Phosphodiesterase inhibitors, such as ibudilast, effectively inhibit pro-inflammatory effects of interferon-b, suggesting possible effects of combination therapy of interferon and phosphodiesterase inhibitors, for the treatment of MS (Kawanokuchi et al., 2004,Feng et al., 2004). Pituitary adenylate cyclase activating polypeptide(PACAP) and radical scavenger, edalabone also suppressed the pro-inflammatory functions of microgiia and ameliorate clinical scores of experimental autoimmune encephalomyelitis (Kato et al., 2004,Banno et al., 2005).Microglia are considered to play a critical role in induction of axonal damage. We have found that microglia disturbed energy production in neurons via secreting glutamate. Thus, suppression of glutamate production by activated microglia may be of use for the future strategy to treat MS patients.