GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation.
Shiina Matsuyama, Reiji Yamamoto, Kaoru Murakami, Nobuhiko Takahashi, Rieko Nishi, Asuka Ishii, Junko Nio-Kobayashi, Nobuya Abe, Kumiko Tanaka, Jing-Jing Jiang, Tadafumi Kawamoto, Toshihiko Iwanaga, Yuta Shinohara, Takeshi Yamasaki, Izuru Ohki, Shintaro Hojyo, Rie Hasebe, Shimpei I Kubota, Noriyuki Hirata, Daisuke Kamimura, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
Journal of immunology (Baltimore, Md. : 1950), 211, 1, 34, 42, 2023年07月01日, ［国際誌］
英語, 研究論文（学術雑誌）, We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common β chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.

Regulation of activated microglia and macrophages by systemically administered DNA/RNA heteroduplex oligonucleotides
Rieko Nishi, Masaki Ohyagi, Tetsuya Nagata, Yo Mabuchi, Takanori Yokota
Molecular Therapy, 30, 6, 2210, 2223, Elsevier BV, 2022年06月, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Microglial activation followed by recruitment of blood-borne macrophages into the central nervous system (CNS) aggravates neuroinflammation. Specifically, in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, activated microglia and macrophages (Mg/Mφ) promote proinflammatory responses and expand demyelination in the CNS. However, a potent therapeutic approach through the systemic route for regulating their functions has not yet been developed. Here, we demonstrate that a systemically injected DNA/RNA heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide (ASO) and its complementary RNA, conjugated to cholesterol (Chol-HDO) distributed more efficiently to demyelinating lesions of the spinal cord in EAE mice with significant gene silencing than the parent ASO. Importantly, systemic administration of Cd40-targeting Chol-HDO improved clinical signs of EAE with significant downregulation of Cd40 in Mg/Mφ. Furthermore, we successfully identify that macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of Chol-HDO by Mg/Mφ of EAE mice. Overall, our findings demonstrate the therapeutic potency of systemically administered Chol-HDO to regulate activated Mg/Mφ in neuroinflammation.

DNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo
Masaki Ohyagi, Tetsuya Nagata, Kensuke Ihara, Kie Yoshida-Tanaka, Rieko Nishi, Haruka Miyata, Aya Abe, Yo Mabuchi, Chihiro Akazawa, Takanori Yokota
Nature Communications, 12, 1, 7344, 7344, Springer Science and Business Media LLC, 2021年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.

【BBB-単なる障壁ではない】正常におけるメカニズム BBBにおける免疫細胞の侵入口形成機構,ゲートウェイ反射について　　　　　　　　　　　　　　　
西 李依子, 村上 薫, 長谷部 理絵, 村上 正晃, Clinical Neuroscience, 40, 12, 1544, 1548, 2022年12月, ［筆頭著者］

自己免疫疾患 層別化する新時代へ 臨床検体のマルチオミクス解析、腸内細菌によって見えてきた免疫経路の全容】(第2章)自己免疫疾患の基盤メカニズムの最新知見 ゲートウェイ反射による自己免疫疾患の制御　　　　　　　　　　　　　　　
村上 薫, 西 李依子, 北條 慎太郎, 田中 勇希, 村上 正晃, 実験医学, 40, 15, 2456, 2466, 2022年09月

免疫介在性神経疾患治療における核酸医薬の可能性　　　　　　　　　　　　　　　
西 李依子, 横田 隆徳, 神経治療学, 38, 4, 484, 488, 2021年, ［筆頭著者］

RNAサイレンシングと神経疾患　　　　　　　　　　　　　　　
西李依子, 永田哲也, 横田隆徳, メディカル・サイエンス・ダイジェスト, 46, 9, 555, 558, 2020年08月, ［筆頭著者］

てんかんとミトコンドリア病
西 李依子, 石橋 哲, 水澤 英洋, 神経眼科, 31, 4, 426, 432, 2014年, ［筆頭著者］
ミトコンドリア病は全年齢層に発症する可能性があり，臨床像や重症度が多彩であるがいくつか代表的な病型がある．エネルギー需要の多い神経系は障害されやすく，中でも難治性てんかんは特徴的な臨床症状の一つで原病の診断のみならず予後との関連も大きい．発症機序は未だ不明な点が多いが，遺伝子変異や生化学的異常など徐々に解明されつつあり症例ごとの遺伝的・生化学的背景を把握する事が治療の選択に重要である．現時点では対症療法が主体であるが，根本的治療法の開発が期待される．, The Japanese Neuro-Ophthalmology Society, 日本語