シンポジウム (Symposia)

神経炎症：脳内環境の破綻がもたらす疾患研究のフロンティア Neuroinflammation: Brain environment in disease
S1-2-1-1 神経の局所的活性化が病原T細胞の中枢神経系へのゲートを形成する Local neural activation creates a gateway for pathogenic T cells in the CNS ○村上正晃¹ ○Masaaki Murakami¹ 大阪大学・生命機能研究科¹ Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Medicine, WPI Immunology Frontier Research Center¹ The old sentence, "all illnesses come from the mind", would suggest important interactions between neural and immune systems in humans. There are at least two types of pathways connecting these systems: the neuro-hormonal axis that depends on circulating hormones and the neural pathways that are mediated by direct synapse networks. A well-studied neuro-hormonal axis is the hypothalamus-pituitary-adrenal axis. Following the activation of this axis, various mediators such as cortisol are secreted, leading to the systemic effects on immune responses. On the other hand, little is known about the local regulation of immune systems by the neural pathways. We have recently reported an example of the neural pathways, which regulates pathogenic CD4 T cell invasion into the CNS via dorsal vessels of the fifth lumber (L5) cord in a murine model of multiple sclerosis (Arima et al., Cell 2012). Persistent stimulation of the soleus muscles by the earth gravity preferentially activates sensory neurons located at L5 cord. Rather than the direct effect on T cells, this continuous activation of the regional neural pathway involving L5 cord modulates the status of the blood vessels to produce chemokines attracting pathogenic CD4 T cells at the specific region. Interestingly, electric stimulation of a certain region of muscles re-directed the accumulation of pathogenic CD4 T cells to blood vessels at the corresponding spinal region connected by sensory neurons of the muscles, suggesting a possibility of artificial manipulations of activated T cell entry into organs of interest. In this symposium, I would like to present recent data about the neural pathways and discuss a future direction of the study field of neuro-immune interactions.	S1-2-1-2 末梢神経損傷により脊髄内移行する免疫系細胞の神経障害性疼痛における役割：TRPM2の関与 Spinally-infiltrated peripheral immune cells in peripheral nerve injury-induced neuropathic pain: Role of TRPM2 ○中川貴之¹, 勇昂一¹, 原口佳代¹, 朝倉佳代子¹, 宗可奈子¹, 白川久志¹, 金子周司¹ ○Takayuki Nakagawa¹, Kouichi Isami¹, Kayo Haraguchi¹, Kayoko Asakura¹, Kanako So¹, Hisashi Shirakawa¹, Shuji Kaneko¹ 京都大学大学院薬学研究科生体機能解析学分野¹ Dept Mol Pharmacol, Grad Sch Pharmaceu Sci, Kyoto Univ, Japan¹ Neuropathic pain is caused by peripheral and central neuroinflammation mediated by the interaction between nociceptive neurons and peripheral immune/spinal glial cells. In addition, recent evidence suggests that peripheral nerve injury leads to infiltration of immune cells, such as macrophages and T-lymphocytes, into the spinal cord. However, the roles of spinally-infiltrated immune cells in neuropathic pain have not been well clarified. We recently reported that TRPM2 channel expressed in macrophages and spinal microglia aggravates pronociceptive inflammatory responses and contributes to neuropathic pain. To further elucidate the roles of TRPM2 expressed in peripheral immune cells, we generated a set of bone marrow (BM) chimeric mice, in which irradiated WT- or TRPM2-KO recipient mice had been transplanted with either WT- or TRPM2-KO donor mice-derived GFP-positive BM cells (TRPM2^BM+/Rec+, TRPM2^BM-/Rec+, TRPM2^BM+/Rec-, TRPM2^BM-/Rec- mice). Mechanical allodynia induced by the partial sciatic nerve ligation in TRPM2^BM-/Rec+, TRPM2^BM+/Rec- and TRPM2^BM-/Rec- mice were significantly attenuated, compared with that in TRPM2^BM+/Rec+ mice. There were no differences in the numbers of GFP-positive BM-derived cells and Iba1/GFP-double positive macrophages in the injured sciatic nerve among chimeric mice 14 days after the nerve injury. In the spinal cord, however, the number of GFP-positive BM-derived cells, especially of GFP/Iba1-double positive macrophages, was significantly decreased in three TRPM2-KO chimeric mice, compared with that in TRPM2^BM+/Rec+ mice, while there was no difference in the numbers of GFP-negative/Iba1-positive resident microglia. These results suggest that TRPM2 plays an important role in the infiltration of macrophages into the spinal cord, resulting the pathogenesis of neuropathic pain, while it plays no or little role in the infiltration of peripheral immune cells into the injured nerves or the activation of spinally resident microglia.
S1-2-1-3 PETによる脳内炎症における活性化ミクログリアのライブイメージング Development of PET molecular probe for live imaging of activated microglia in neuroinflammation ○尾上浩隆¹, 宿里充穂^1,2, 高島平野好聖^1,3, 土居久志¹, 鈴木正昭¹, 渡辺恭良¹ ○Hirotaka Onoe¹, Miho Shukuri^1,2, Misato Takashima-Hirano^1,3, Hisashi Doi¹, Masaaki Suzuki¹, Yasuyoshi Watanabe¹ 理化学研究所分子イメージング科学研究センター¹, （独）国立精神・神経医療研究センター・分子イメージング研究部², 浜松医大・メディカルフォトニクス研究センター³ RIKEN Center for Molecular Imaging Science¹, National Center of Neurology and Psychiatry, Kodaira, Japan², Medical Photonics Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan³ Neuroinflammation responding as a host defense mechanism is known to be involved in various neurological and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so on. In order to develop the imaging probe for "Live imaging" (in vivo monitoring) during the process of neuroinflammation by positron emission tomography (PET), we have labeled a series of 2-arylpropionic acid derivatives of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX) inhibitors, with ¹¹C since COX enzymatic activity has been known to be critically involved in a cascade of inflammatory process. Among ¹¹C-radiolabeled NSAIDs, we characterized the specificity of ¹¹C-Ketoprofen-methyl ester (¹¹C-KTP-Me), and determined the involvement of COXs in neuroinflammatory process in vivo condition. In PET studies, increased ¹¹C-KTP-Me accumulation was observed in the inflamed hemisphere of rats, which were intracranially injected lipopolysaccharide (LPS). Changes in ¹¹C-KTP-Me accumulation peaked at day 1 after the injury, at which COX-1 but not COX-2 expression was increased in the activated microglia. Time-course of ¹¹C-KTP-Me was closely corresponded to that of changes in number of COX-1 expressing activated microglia in the inflamed area, strongly indicating that ¹¹C-KTP-Me might be a COX-1 selective PET probe. For further improvement of specificity, we recently succeeded to obtain S-enantiomer of ¹¹C-KTP-Me by chiral separation, and proved its higher specificity for COX-1 than R-enantiomer. ¹¹C-KTP-Me should be a useful PET probe for live imaging during the process of neuroinflammation, especially for monitoring of microglia activation.	S1-2-1-4 中枢神経系に浸潤する免疫系細胞とグリア連関の神経変性病態への役割 Infiltrating immune cells-glia communication in neurodegenerative disease ○山中宏二¹ ○Koji Yamanaka¹ 名古屋大学環境医学研究所¹ Research Institute of Environment Medicine, Nagoya University¹ Dominant mutations in the Cu/Zn superoxide dismutase (SOD1) gene lead to a familial form of amyotrophic lateral sclerosis (ALS). Although ubiquitous expression of mutant SOD1 provokes progressive, selective motor neuron degeneration in human and rodents due to an acquired toxic property (ies) of the mutant, the roles of mutant toxicity within microglia and astrocytes in disease progression were established by our cell-type specific gene ablation from mutant SOD1 mice, indicating that glial cells contribute to non-cell autonomous neurodegeneration. Analysis of misregulated genes within glial cells that we isolated from the spinal cords of symptomatic mutant SOD1 mice as well as sporadic ALS patients, indicated the involvement of innate immune system. The inhibition of innate immune system by eliminating TRIF (TIR domain-containing adaptor inducing IFN-β), an essential adaptor for Toll-like receptor signaling, from SOD1^G93A mice significantly accelerated disease progression with altered expression of chemokines in the spinal cord. By contrast, blocking MyD88-dependent innate immune pathway exhibited marginal effect on the onset and survival time of ALS mice. Further, we observed the defective chemokines, and decreased number of infiltrating lymphocytes and other immune cells in TRIF deficient SOD1^G93A mouse spinal cords, the findings may explain the accelerated disease progression. These results indicate the active role of microglia-innate immune system communication in modifying disease progression in ALS models.
S1-2-1-5 グリアが起点となる脳内環境変化 Glia-initiated brain environmental changes ○田中謙二¹ ○Kenji Tanaka¹ 慶應義塾大学医学部精神神経科学教室¹ Department of Neuropsychiatry, Keio University School of Medicine¹ Brain environmental changes in the inflammatory process are the consequence of cellular responses in situ; Neurons, glia, vascular cells and immune cells interact respectively and each interaction is intermingled in a complex manner. Furthermore, the interaction consists of "glia to other cell types" and "other cell types to glia" unidirectional actions. Thus the dissection of complex actions is necessary to understand how brain comprising cells behave in the inflammatory process. To highlight astrocyte-initiated changes within complex responses, we have established the tool for selective manipulation of astrocytes by virtue of optogenetics. We generated transgenic animals in which channelrhodopsin-2 (ChR2) was selectively expressed in astrocytes. The expression levels of ChR2 were high enough to trigger the photocurrents in astrocytes in acute slice preparations. We then examined the consequences of astrocytic manipulation in vivo, in this case current injection via ChR2. We illuminated the dorsal cortex and examined c-fos induction. Without fiber insertion to the brain parenchyma, c-fos induction took place only in the astrocytes, suggesting the absence of unidirectional astrocyte to neuron action. Hence, with fiber insertion to the brain parenchyma, c-fos was induced in adjacent neuronal cells as well, suggesting astrocyte-initiated neuronal excitation requires injury-related environmental changes. Expanding repertoire of optogenetically targeted cells, such as vascular cells or immune cells, permits us to further dissect causes leading environmental changes.

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