一般ポスター
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| 7月7日（金） 13:50-14:50 ポスター会場①
2P③-1
GDF-15はミクログリアを介した炎症を誘発する
Growth differentiation factor (GDF)-15 induced pro-inflammatory states of microglia
山本 温人1, 宮上 紀之1, Mohammed E. Choudhury2, 田中 潤也2, 永井 将弘1
1. 愛媛大学大学院医学系研究科 臨床薬理学, 2. 愛媛大学大学院医学系研究科 分子細胞生理学
Haruto Yamamoto1, Noriyuki Miyaue1, Mohammed E. Choudhury2, Junya Tanaka2, Masahiro Nagai1
1. Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Ehime, Japan, 2. Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Ehime, Japan
Growth differentiation factor 15 (GDF-15) is released in response to various stressors. Our recent study showed elevated serum GDF-15 in patients with Parkinson's disease (PD). PD is a neuroinflammatory disease, but little is known about GDF-15 in aspects of the neuroinflammatory process of this disease. The aim of this study is to investigate the involvement of GDF-15 in the neuroinflammation of PD brain, with a particular focus on microglia. Primary microglia were used where exposure of GDF-15 for overnight increased nitrite release as revealed by Griess assay. In addition, the mitochondrial bioenergetic profiles of microglial cells demonstrated that GDF-15 treatment markedly increased the proton leak and decreased coupling efficiency. Flow cytometric analysis showed Increased expression of microglial proinflammatory markers namely CD11b and CD45 in primary cultured microglia following exposure of GDF-15. In addition to this, qPCR analysis with primary cultured microglia showed GDF-15 addition increased IL-1β and CD32 mRNAs expression. Furthermore, GDF-15 administration in adult rats for 24 hours increased mRNA expression of inflammatory markers CD32 and IL1β in sorted microglia. Altogether, our findings of present study suggest that GDF15 polarizes microglia towards pro-inflammatory types through inducing mitochondrial stress of microglia. | | 7月7日（金） 13:50-14:50 ポスター会場①
2P③-2
脳梗塞後の壊死組織内に出現するミクログリアの機能
Role of novel microglia induced in necrotic tissue after cerebral ischemia
澤野 俊憲1, 孫 海洋1, 中谷 仁1, 稲垣 忍2,3, 中込 隆之4,5, 松山 知弘5, 田中 秀和1
1. 立命大 生命 薬理, 2. 阪大 連合小児 分子生物遺伝学, 3. 行岡医大 理療, 4. 兵医大 先端研 神再, 5. 兵医大 先進脳
Toshinori Sawano1, Haiyang Sun1, Jin Nakatani1, Shinobu Inagaki2,3, Takayuki Nakagomi4,5, Tomohiro Matsuyama5, Hidekazu Tanaka1
1. Pharmacol. Lab., Dept. Biomed. Sci., Ritsumeikan Univ., Shiga, Japan, 2. Dept. Child Dev. and Mol. Brain. Sci., United Grad. Sch. Child Dev., Osaka Univ., Osaka, Japan, 3. Dept. PT., Yukioka Col. Health Sci., Osaka, Japan, 4. Lab. Neurogenesis and CNS Repair., Inst. Adv. Med. Sci., Hyogo Med. Univ., Hyogo, Japan, 5. Dept. Therap. Prog. Brain Dis., Hyogo Med. Univ., Hyogo, Japan
Cerebral ischemia leads to liquefactive necrosis. The liquefied area contains various types of neurotoxic components. Thus, effective clearance of necrotic debris is important for non-necrotic areas to maintain homeostasis. We previously demonstrated that ischemia-induced multipotent stem cells (iSCs) are induced in the necrotic area after cerebral ischemia, and iSCs differentiate into microglia. In both physiological and pathological conditions, microglia play a pivotal role in waste clearance from the central nervous system. However, functional properties of iSCs-derived microglia are not clear. In this study, transcriptome analysis revealed that iSCs-derived microglia abundantly expressed genes related to the vascular growth. Histological analysis showed that endothelial cells proliferation was significantly upregulated in the necrotic area at 3 days after middle cerebral artery occlusion (MCAO). Microglial depletion by PLX3397 administration leads to the significant decrease in the MCAO-induced endothelial cells proliferation, suggesting that iSCs-derived microglia involve in the vascular remodeling in the necrotic tissue. We expect that these remodeling induced by microglia can contribute to the providing the routes for necrotic tissue drainage. | | 7月7日（金） 13:50-14:50 ポスター会場①
2P③-3
貪食チェックポイントSIRPαの欠損によるCD11ｃ陽性ミクログリア出現の領域特異性解析
Region-specificity of the emergence of CD11c+ microglia due to lack of the phagocytic checkpoint molecule SIRPα
尾池 恵摘1, 水谷 瑠依1, 今井 武史1, 榛澤 春哉1, 堀 鮎香1, 浦野 江里子1, 松本 映子1, 神宮 大輝2, 林 由里子2, 的崎 尚3, 大西 浩史1
1. 群馬大学大学院 保健学研究科 生体情報検査科学講座, 2. 群馬パース大学 保健科学研究科, 3. 神戸大学大学院 医学研究科
Etsumi Oike1, Rui Mizutani1, Takeshi Imai1, Shunya Hanzawa1, Ayuka Hori1, Eriko Urano1, Eiko Matsumoto1, Daiki Jingu2, Yuriko Hayashi2, Takashi Matozaki3, Hiroshi Ohnishi1
1. Gunma Univ Grad Sch Health Sci, Gunma, Japan, 2. Gunma Paz Univ Grad Sch Health Sci, Gunma, Japan, 3. Kobe Univ Grad Sch Med, Kobe, Japan
Microglia, macrophage-like cells in the brain express a membrane protein SIRPα that acts as a phagocytic checkpoint in macrophages. In microglia-specific SIRPα conditional knockout (MG-SIRPα cKO) mice, CD11c+ microglia (CD11c+ MG), which are rarely observed in normal brain, appear specifically in brain white matter. Several studies have reported that CD11c+ MG appear in association with the pathogenesis of demyelination or other neurodegenerative diseases. Interestingly, MG-SIRPα cKO mice are resistant to a demyelination model. Thus, CD11c+ MG may be protective against tissue damage, and SIRPα may act as a checkpoint for the protective activation of microglia. Preliminary analysis indicated that the emergence of CD11c+ MG in the brain of MG-SIRPα cKO mice is ununiform in white matter. Here, we examine the region specificity of the emergence of CD11c+ MG in MG-SIRPα cKO mice. Immunohistochemical analyses revealed that CD11c+ MG appeared prominently in regions such as the hippocampal fimbria, optic tectum, and corpus callosum bordering the ventricles. In addition, CD11c+ MG were observed in the subfornical organ, one of the periventricular organs, even in normal control mice that do not lack SIRPα. We are currently investigating the relationship between the characteristics of these regions and the mechanism by which SIRPα suppresses CD11c+ MG. | | 7月7日（金） 13:50-14:50 ポスター会場①
2P③-4
脳保護作用が期待されるSIRPα欠損ミクログリアの細胞特性の解析
Analysis of characteristics of SIRPα-deficient microglia with potential brain protective effects
水谷 瑠依1, 尾池 恵摘1, 榛澤 俊哉1, 今井 武史1, 富山 飛鳥1, 浦野 江里子1, 松本 映子1, 林 由里子2, 的崎 尚3, 大西 浩史1
1. 群馬大学大学院 保健学研究科 生体情報検査科学講座, 2. 群馬パース大学大学院 保健科学研究科, 3. 神戸大学大学院 医学研究科
Rui Mizutani1, Etsumi Oike1, Shunya Hanzawa1, Takeshi Imai1, Asuka Tomiyama1, Eriko Urano1, Eiko Matsumoto1, Yuriko Hayashi2, Takashi Matozaki3, Hiroshi Ohnishi1
1. Gunma Univ Grad Sch Health Sci, Gunma, Japan, 2. Gunma Paz Univ Grad Sch Health Sci, Gunma, Japan, 3. Kobe Univ Grad Sch Med, Kobe, Japan
CD11c+ microglia (MG) are rarely found in the normal mouse brain but are observed in neurodegenerative disease and aging. CD11c+ MG subsets such as Disease-Associated Microglia (DAM), have been predicted to have protective functions against neurodegenerative diseases and aging. SIRPα (Signal regulatory protein α) is a transmembrane protein expressed in MG. In MG-specific SIRPα conditional knockout (MG-SIRPα cKO) mice, CD11c+ MG spontaneously appear in white matter regions. MG-SIRPα cKO mice show resistance to demyelination and age-related motor learning deficits, suggesting that SIRPα-deficient MGs may have a protective effect against white matter lesions and age-related brain tissue damage. We performed transcriptome analysis of the white matter tissues of MG-SIRPα cKO mice. The gene expression profile of the white matter tissue of MG-SIRPα cKO is similar to that of aged wild-type mice, and many DAM signature genes were increased in the MG-SIRPα cKO sample. Among them, GPNMB and TREM2 were confirmed to be expressed in MG by immunostaining analysis, suggesting that SIRPα-deficient MGs likely have a DAM-like gene expression profile. We further analyzed MG isolated from aged mouse brains and identified genes differentially expressed in SIRPα-deficient MG when compared with control mouse MG after aging. The expression of these gene products in MG is currently being examined. | | 7月7日（金） 13:50-14:50 ポスター会場①
2P③-5
オンコスタチンM静脈内投与による最後野内神経細胞およびミクログリアの活性化
Activation of neurons and microglia in the area postrema by intravenous administration ofoncostatin M
坂之上 徳博, 郷 夏海, 南 雅文
北海道大学 薬学部 薬学科 薬理学研究室
Norihiro Sakanoue, Natsumi Go, Masabumi Minami
Faculty of Pharmaceutical Sciences, Dept. of Pharmacy, Hokkaido Univ., Hokkaido, Japan
The blood-brain barrier (BBB) regulates molecular traffic from the blood to the brain parenchyma and maintains CNS homeostasis. The BBB dysfunction has been reported to be associated with neuropsychiatric disorders such as major depression. We have shown treatment with IL-6 family cytokines, oncostatin M (OSM), attenuates the BBB function in vitro, i.v. administration of OSM increases Evans blue fluorescence intensity in the area postrema (AP) and induces depression-like behavior in vivo.
In this study, we examined the activation of neurons and microglia in the AP by i.v. administration of OSM to male BALB/c mice (7-8 weeks old). First, OSM (1 μg/100 μL/individual) or saline was administered via tail vein. Then, 1, 2, 4, 8, and 24 hours after administration, trans cardiac perfusion was performed. We removed and fixed brain in 4% PFA, and prepared 40 μm-thick sections in cryostat. We used c-Fos and Iba1 antibodies, respectively. Microscopic images were analyzed using ImageJ. The results showed 1 hour after OSM administration, there was an increasing trend in c-Fos expression compared to the control. Also, 8 hours after OSM administration, a trend of activation with morphological change of microglia was observed compared to the saline group. These results suggest increased blood OSM concentration induces activation of neurons and microglia in AP. | | 7月7日（金） 13:50-14:50 ポスター会場①
2P③-6
SARS-Cov-2 スパイク蛋白に対するinduced microglia-like cells (iMG細胞)の反応性の解析
Inflammatory effects of SARS-Cov-2 spike S1 subunit: Translational research using induced microglia-like cells
久良木 聡太1, 稲嶺 翔吾1, 平野 羊嗣2, 扇谷 昌宏1,3, 中尾 智博1, 加藤 隆弘1
1. 九州大学大学院医学研究院 精神病態医学, 2. 宮崎大学医学部 臨床神経科学講座 精神医学分野, 3. 旭川医科大学 解剖学教室
Sota Kyuragi1, Shogo Inamine1, Yoji Hirano2, Masahiro Ohgidani1,3, Tomohiro Nakao1, Takahiro Kato1
1. Department of Neuropsychiatry, Graduate school of Medical Sciences, Kyushu University, Fukuoka, Japan, 2. Department of Psychiatry, Faculty of Medicine, University of Miyazaki, 3. Asahikawa Medical University, Department of Functional Anatomy and Neuroscience.
The psychiatric side effect of mRNA COVID-19 vaccine, which encodes SARS-Cov-2 spike protein, is an issue to be examined. Recently, SARS-Cov-2 spike S1 subunit has been reported to have neuroinflammatory effects in rodent study1. Although there are many technical and ethical difficulties in study focused on the human brain, induced microglia-like cells (iMG) can be a useful tool as surrogating cells for microglia2. Herein, we conducted translational research using iMG from patient whose psychiatric symptoms were worsened after vaccination and improved while taking minocycline.We comprehensively compared the differences in mRNA expression pattern in response to S1 stimulation by RNA sequencing in iMG cells derived from healthy subject and a patient. Patient-derived iMG showed higher expression of genes related to immune, some of which were suppressed while taking minocycline.The results of this study suggest that hyper reactivity to the SARS-Cov-2 spike protein and inflammation in the brain may be involved in the exacerbation of psychiatric symptoms after vaccination. Further studies are needed to elucidate the pathophysiology.Reference1. Frank MG et al, Brain Behav Immun 2022. 2. Ohgidani et al, Sci Rep 2014 | |
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