TOP ＞ Symposium

Symposium 6 Pathomechanism of neurologic diseases based on interaction between immune cells and glia シンポジウム6 日本神経学会／日本神経化学会ジョイントシンポジウム 免疫細胞とグリアの相互作用からみた神経疾患の病態 SY6-1 Interaction between glial and endothelial cells on the blood-brain barrier and breakdown of the blood-brain barrier in neurological diseases 血液脳関門でのグリア-内皮細胞間の相互作用と神経疾患での血液脳関門破綻 Shimizu Fumitaka（清水 文崇），神田 隆 Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan The blood-brain barrier (BBB) acts as a physical and functional barrier that separates the vulnerable environment of the central nervous system (CNS) from the peripheral circulation. It also plays important roles in regulating the import and export of necessary substances to maintain homeostasis in the brain. The BBB is very tightly regulated by brain endothelial cells lining the lumen of brain vasculature, pericytes embedded within abluminal basement membrane, and astrocytes with their endfeet directly contacting these two cells, and two basement membranes. Cross-talk between these 3 cells with neuron is essential for maintaining the physiological BBB characteristics, termed as the neurovascular unit (NVU). Histopathological analysis of various neurologic diseases, including Alzheimer diseases, multiple sclerosis and neuromyelitis optica, demonstrated that BBB disruption is a common feature, suggesting that a functional BBB is required for a healthy CNS. Recent researches using our human BBB-cell lines (brain endothelial cells, pericytes and astrocytes) or another primary/immortalized BBB-cell lines have contributed to the understanding of the molecular mechanism in the BBB under physiological and pathological conditions.In this presentation, three recent topics will be discussed: (1) how BBB is regulated by glial cells in normal condition and what cell types mainly contribute to the regulation of BBB function, (2) what happens in BBB under neurological disease, such as neuromyelitis optica, multiple sclerosis and Alzheimer disease, (3) how we can use knowledge of the molecular and cellular networks that make up the NVU in order to repair pathological BBB in neurological diseases and deliver the effective drugs across the intact BBB. SY6-2 Elucidation of the effects of gap junction protein connexin on the pathogenesis of multiple sclerosis model mice and development of new therapeutic options by functional modification ギャップ結合蛋白コネキシンが多発性硬化症モデルマウスの病態に及ぼす影響の解析とその機能修飾による治療法開発の試み Yamasaki Ryo（山崎 亮），趙 奕南，ヴァイエリン マリオン，方 梅，宇根 隼人，山口 浩雄，吉良 潤一 Dept. Neurol., Kyushu Univ. Objective: We previously reported that astroglial connexin (Cx)43 and oligodendroglial Cx32 and Cx47 were frequently lost in acute and chronic lesions of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, the roles of glial Cxs in these demyelinating diseases remain to be established. We therefore aimed to clarify glial Cxs’ roles in demyelination using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Cxs-deficient mice. Methods: Tamoxifen was administrated into Plp1-CreERT;Cx47 fl/fl mice to allow tamoxifen-inducible oligodendroglia-specific conditional Cx47 knock-out (Cx47 icKO) mice. We also used GLAST-CreERT;Cx43 fl/fl mice for astroglia-specific inducible Cx43 knock-out (Cx43 icKO) mice. Cx30 knock-out (Cx30 KO) mice, Cx47 icKO mice and Cx43 icKO mice were used together with their control littermates for induction of EAE by myelin oligodendrocyte glycoprotein (MOG). Results: EAE was markedly attenuated in the chronic but not acute phase of EAE in Cx30 KO mice, which showed less demyelination and diffuse activation of microglia. These microglia had down-modulation of Toll-like receptor 4 and an M2 phenotype by microarray analysis and immunohistochemistry. Cx43 icKO mice also showed milder phenotype with astroglial A2-deviation. By contrast, Cx47 iKO mice showed more severe EAE at the acute as well as chronic phases.Interpretation: Absence of astroglial Cx30 or Cx43 ameliorate EAE while absence of oligodendroglial Cx47 exacerbates EAE, suggesting that astroglial and oligodendroglial Cxs differentially modulate EAE severity. SY6-3 Glia-immune communication in Amyotrophic Lateral Sclerosis 筋萎縮性側索硬化症における免疫·グリア連関 Yamanaka Koji（山中 宏二） Researchi Institute of Environmental Medicine, Nagoya University There are accumulating evidence that glia-immune interaction play a role in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). However, the relationship between the innate and acquired immunity and the neuroinflammation affecting disease processes in ALS was not fully investigated. To clarify the role of the peripheral immune environment in ALS disease course, we generated two strains of SOD1-ALS mice derived from different genetic backgrounds, C57BL/6 and Balb/c, known to have Th1- and Th2- dominant immune environments, respectively. Balb/c-ALS mice exhibited the shorter survival with a lower expression of IGF-I and fewer infiltrating immune cells and activated microglia in spinal cords. On the other hand, we also found that deficiency of innate immune adaptor TRIF significantly shortened survival times with acceleration of disease progression of SOD1-ALS mice. Despite of dominant roles of MyD88 in Toll-like receptor signaling, MyD88 had a marginal impact on disease course of ALS. TRIF signaling also regulates the number of infiltrating immune cells into the spinal cords of ALS mice. In addition, aberrantly activated astrocytes, expressing Mac2, p62, and apoptotic markers, were accumulated in the lesions of TRIF-deficient ALS mice. These findings suggest that TRIF pathway plays an important role in protecting the brain environment by eliminating abnormal glial cells. Both studies suggest that a neuroprotective brain environment is maintained by glia-immune communications, and uncovered a novel role of TRIF in ALS. SY6-4 Glia-targeting therapy for neurological disorders グリアを標的とした神経疾患の治療法開発 Takeuchi Hideyuki（竹内 英之） Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan The ratio of glia/neuron explosively increases as revolution. It contributes to the complexity of the nervous system in human, in other words, it may lead to the complexity of neurological disorders in human. The nervous system has long been considered as an immunological privileged site where the surveillance of the immune system does not reach out. However, a recent evidence shows that the pathological condition induces dysfunction of neuronal/glial cells and infiltration of inflammatory cells, resulting in disruption of homeostasis in the nervous system. Especially, harmful glial activation fuels a vicious spiral of chronic neuroinflammation and neurodegeneration in various neurological disorders. Here we introduce that “blockade of gap junction/hemichannel” and “glial phenotype conversion” may be a promising therapeutic strategy for neurological disorders to halt chronic neuroinflammation and neurodegeneration.