愛情ホルモン・オキシトシンによる炎症免疫抑制作用の分子基盤の解明

• Project/Area Number: 21H02695
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kanazawa University
• Principal Investigator: 山本 靖彦 金沢大学, 医学系, 教授 (20313637)
• Co-Investigator(Kenkyū-buntansha): 棟居 聖一 金沢大学, 医学系, 助教 (10399040) ; 木村 久美 金沢大学, 医学系, 助教 (60409472) ; 松下 貴史 金沢大学, 医学系, 教授 (60432126)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: オキシトシン / 制御性B細胞 / 炎症

Outline of Research at the Start

オキシトシンの炎症抑制効果について、特に、B細胞集団の中で免疫反応を抑制する制御性B細胞の分化誘導に注目し、全身性エリテマトーデスマウスモデルを用いて研究を進める。オキシトシンによる炎症免疫抑制作用や自己抗体産生抑制効果について、オキシトシン受容体依存的な観点から追究するとともに、オキシトシン受容体によらない非依存的経路についても研究を進め、その全貌を解明することで新しい概念を提唱する。

Outline of Annual Research Achievements

オキシトシンは、脳視床下部の神経内分泌細胞で合成され、下垂体後葉から循環血液中に放出されるペプチドホルモンである。その抹消作用として、陣痛誘発時の子宮収縮や授乳時の乳汁分泌作用、最近では、中枢神経作用である信頼や愛情の形成に関わることも知られてきた。また、オキシトシンの免疫系への作用として、抗炎症効果や免疫抑制作用が報告されているが、その分子作用メカニズムに関しては全く不明であった。本研究では、そのようなオキシトシンの免疫制御作用について、オキシトシン受容体依存的な観点から研究を行うとともに、オキシトシン受容体非依存的な効果についても調べ、その分子機構の全貌を明らかにすることを目的とする。
本研究において、まず全身性エリテマトーデス（SLE）マウスモデル（MRL/lprマウス）を使って、オキシトシン持続投与を行うと、SLEの病態は抑制され、その有効性が示された。免疫細胞におけるオキシトシン受容体の発現は、一部のB細胞サブセットで確認できた。MRL/lprマウスの遺伝背景に、オキシトシン受容体欠損を導入したマウスを作製し観察すると、骨髄におけるB細胞分化が障害され、末梢血中のB細胞画分の低下が認められた。そして、SLEの病態は軽快しており、予想に反した表現系を示した。また、オキシトシンと結合するタンパク質の解析では、補体C4が同定でき、両者の直接の結合も確認できた。現在は、補体C4を介する炎症や自己免疫作用に関する機序の解明や、C4ノックアウトマウスの作製とその表現型の解析を進めているところである。マウスには、補体C4を作り出す遺伝子が２つ（SlpとC4）あり、Slp単独欠損、もう片方のC4単独欠損、そしてSlp/C4両欠損マウスの作製を行い解析を行っている。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

当初の予定通り、オキシトシン投与による全身性エリテマトーデス（SLE）マウスモデル（MRL/lprマウス）への有効性が確認できた。さらに、オキシトシン受容体を発現する免疫細胞を同定することができた。遺伝背景がMRL/lprマウスに、オキシトシン受容体欠損を導入したマウスの作製にも成功し、その病態解析も進んでいる。オキシトシンに結合する血清タンパク質・補体C4も新たに発見し、補体C4を作り出す２つの遺伝子（SlpとC4）の欠損マウスの作製とその解析を行っている。現在のところ順調に研究が進んでいる。

Strategy for Future Research Activity

今後の研究の進め方については、当初の計画通りに進めて行く予定である。オキシトシン受容体依存的な観点からは、オキシトシン受容体を発現するB細胞のさらに詳細な解析を進め、B細胞がどのように炎症に対して抑制的に働くのかを調べていく。オキシトシン受容体欠損により、どのように骨髄におけるB細胞分化が障害されるのかを明らかにしていく。そして、B細胞の分化、特に、形質細胞への分化と自己抗体産生抑制に関わる機構を明らかにしていく。また、オキシトシン受容体非依存的な効果については、補体C4を介する作用機序の解明や、補体C4を作り出す２つの遺伝子（SlpとC4）の欠損マウスの作製とその解析を進めていく予定である。

Research Products

• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] 順天郷大学校(韓国)
• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] 順天郷大学校(韓国)
• [Journal Article] Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake (2023)
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• [Journal Article] A nonsteroidal anti-inflammatory drug, zaltoprofen, inhibits the growth of extraskeletal chondrosarcoma cells by inducing PPARγ, p21, p27, and p53 (2023)
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  • Journal Title: Cell Cycle Volume: 22 Issue: 8 Pages: 939-950
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• [Journal Article] The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice (2023)
  • Author(s): Inaba Yuka、Hashiuchi Emi、Watanabe Hitoshi、Kimura Kumi、Oshima Yu、Tsuchiya Kohsuke et al.
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• [Journal Article] Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps (2023)
  • Author(s): Watanabe Haruki、Kubo Masataka、Taniguchi Akihiko、Asano Yosuke、Hiramatsu-Asano Sumie、Ohashi Keiji、Zeggar Sonia、Katsuyama Eri、Katsuyama Takayuki、Sunahori-Watanabe Katsue、Sada Ken-ei、Matsumoto Yoshinori、Yamamoto Yasuhiko、Yamamoto Hiroshi、Son Myoungsun、Wada Jun
  • Journal Title: Clinical Immunology Volume: 250 Pages: 109317-109317
  • DOI: 10.1016/j.clim.2023.109317
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• [Journal Article] Correction to: Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis. (2022)
  • Author(s): Takei R, Miyashita T, Takada S, Tajima H, Ninomiya I, Takamura H, Fushida S, Harashima A, Munesue S, Yagi S, Inaki N, Ohta T, Yamamoto Y.
  • Journal Title: Cancer Immunol Immunother. Volume: 71 Issue: 4 Pages: 791-793
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• [Journal Article] Use of Cocultures to Measure the Blood-Brain Barrier Permeability of Oxytocin. (2022)
  • Author(s): Yamamoto Y, Harashima A, Munesue SI, Higashida H.
  • Journal Title: Methods Mol Biol. Volume: 2384 Pages: 247-255
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• [Journal Article] Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model. (2022)
  • Author(s): Yamazaki H, Tajima H, Yamamoto Y, Munesue S, Okazaki M, Ohbatake Y, Nakanuma S, Makino I, Miyashita T, Takamura H, Ohta T.
  • Journal Title: Mol Med Rep. Volume: 25 Issue: 6 Pages: 201-201
  • DOI: 10.3892/mmr.2022.12717
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• [Journal Article] Evolution and diabetic vasculopathy (2022)
  • Author(s): Yamamoto Hiroshi、Yamamoto Yasuhiko
  • Journal Title: Journal of Diabetes Investigation Volume: 13 Issue: 7 Pages: 1111-1113
  • DOI: 10.1111/jdi.13843
  • Peer Reviewed
• [Journal Article] Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation (2022)
  • Author(s): Hayashi Kenjiro、Sato Koichi、Ochi Seishi、Kawano Shuhei、Munesue Seiichi、Harashima Ai、Oshima Yu、Kimura Kumi、Kyoi Takashi、Yamamoto Yasuhiko
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 10 Pages: 5757-5757
  • DOI: 10.3390/ijms23105757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET (2022)
  • Author(s): Shirasaki Takayoshi、Yamagoe Satoshi、Shimakami Tetsuro、Murai Kazuhisa、Imamura Ryu、Ishii Kiyo-Aki、Takayama Hiroaki、Matsumoto Yukako、Tajima-Shirasaki Natsumi、Yamashita Taro、Yoshikawa Tomoki、Takimoto Kazuhiro、Kaneko Shuichi、Matsumoto Kunio、Takamura Toshinari、Honda Masao
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 3176-3176
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• [Journal Article] Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4 (2022)
  • Author(s): Katagiri Takamasa,Espinoza Luis,Uemori Mizuho,Ikeda Honoka,Hosokawa Kohei,Ishiyama Ken,Yoroidaka Takeshi,Imi Tatsuya,Takamatsu Hiroyuki,Ozawa Tatsuhiko,Kishi Hiroyuki,Yamamoto Yasuhiko,Elbadry Mahmoud,Yoshida Yoshinori,Chonabayashi Kazuhisa,Takenaka Katsuto,Akashi Koichi,Nannya Yasuhito,Ogawa Seishi,Nakao Shinji
  • Journal Title: eJHaem Volume: 3 Issue: 3 Pages: 669-680
  • DOI: 10.1002/jha2.515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Receptor for advanced glycation end-products and child neglect in mice: A possible link to postpartum depression (2022)
  • Author(s): Higashida H, Gerasimenko M, Yamamoto Y.
  • Journal Title: Comprehensive Psychoneuroendocrinology Volume: 11 Pages: 100146-100146
  • DOI: 10.1016/j.cpnec.2022.100146
  • Peer Reviewed / Open Access
• [Journal Article] Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside (2022)
  • Author(s): H. Higashida, K. Furuhara, O. Lopatina, M. Gerasimenko, O. Hori, T. Hattori, Y. Hayashi, S. M. Cherepanov, A. A. Shabalova, A. B. Salmina, K. Minami, T. Yuhi, C. Tsuji, P. Y. Fu, Z. Liu, S. Luo, A. Zhang, S. Yokoyama, S. Shuto, M. Watanabe, K. Fujiwara, S. Munesue, A. Harashima, Y. Yamamoto
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 858070-858070
  • DOI: 10.3389/fnins.2022.858070
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway (2022)
  • Author(s): Matsumoto T, Iizuka T, Nakamura M, Suzuki T, Yamamoto M, Ono M, Kagami K, Kasama H, Wakae K, Muramatsu M, Horike SI, Kyo S, Yamamoto Y, Mizumoto Y, Daikoku T, Fujiwara H.
  • Journal Title: Cancer Sci. Volume: 113 Issue: 10 Pages: 3376-3389
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  • Peer Reviewed / Open Access
• [Journal Article] RAGE activation in macrophages and development of experimental diabetic polyneuropathy (2022)
  • Author(s): Osonoi Sho、Mizukami Hiroki、Takeuchi Yuki、Sugawa Hikari、Ogasawara Saori、Takaku Shizuka、Sasaki Takanori、Kudoh Kazuhiro、Ito Koichi、Sango Kazunori、Nagai Ryoji、Yamamoto Yasuhiko、Daimon Makoto、Yamamoto Hiroshi、Yagihashi Soroku
  • Journal Title: JCI Insight Volume: 7 Issue: 23
  • DOI: 10.1172/jci.insight.160555
  • Peer Reviewed / Open Access
• [Journal Article] Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury (2022)
  • Author(s): Miyagawa Taro、Iwata Yasunori、Oshima Megumi、Ogura Hisayuki、Sato Koichi、Nakagawa Shiori、Yamamura Yuta、Kamikawa Yasutaka、Miyake Taito、Kitajima Shinji、Toyama Tadashi、Hara Akinori、Sakai Norihiko、Shimizu Miho、Furuichi Kengo、Munesue Seiichi、Yamamoto Yasuhiko、Kaneko Shuichi、Wada Takashi
  • Journal Title: Biology Open Volume: 11 Issue: 1 Pages: 1-8
  • DOI: 10.1242/bio.058852
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diabetes in humans activates pancreatic stellate cells via RAGE in pancreatic ductal adenocarcinoma. (2022)
  • Author(s): Uchida C, Mizukami H, Hara Y, Saito T, Umetsu S, Igawa A, Osonoi S, Kudoh K, Yamamoto H, Yagihashi S, Hakamada K
  • Journal Title: Int J Mol Sci Volume: 22 Issue: 21 Pages: 11716-11716
  • DOI: 10.3390/ijms222111716
  • Peer Reviewed / Open Access
• [Journal Article] Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond. (2022)
  • Author(s): Oshima Y, Harashima A, Munesue S, Kimura K, Leerach N, Goto H, Tanaka M, Niimura A, Hayashi K, Yamamoto H, Higashida H, Yamamoto Y.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 4 Pages: 2086-2086
  • DOI: 10.3390/ijms23042086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transport of oxytocin to the brain after peripheral administration by membrane-bound or soluble forms of receptors for advanced glycation end-products. (2021)
  • Author(s): Munesue S, Liang MingKun, Harashima A, Zhong J, Furuhara K, Boitsova E, Cherepanov SM, Gerasimenko M, Yuhi T, Yamamoto Y, Higashida H.
  • Journal Title: J Neuroendocrinol Volume: 33 Issue: 3
  • DOI: 10.1111/jne.12963
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lipopolysaccharides induce a RAGE-mediated sensitization?of sensory neurons and fluid hypersecretion in the upper airways (2021)
  • Author(s): Nair Manoj、Jagadeeshan Santosh、Katselis George、Luan Xiaojie、Momeni Zeinab、Henao-Romero Nicolas、Chumala Paulos、Tam Julian S.、Yamamoto Yasuhiko、Ianowski Juan P.、Campanucci Ver?nica A.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 8336-8336
  • DOI: 10.1038/s41598-021-86069-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Receptor for advanced glycation end-products (RAGE) plays a critical role in retrieval behavior of mother mice at early postpartum. (2021)
  • Author(s): Gerasimenko M, Lopatina O, Munesue S, Harashima A, Yokoyama S, Yamamoto Y, Higashida H.
  • Journal Title: Physiol Behav Volume: 235 Pages: 113395-113395
  • DOI: 10.1016/j.physbeh.2021.113395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RAGE signaling antagonist suppresses mouse macrophage foam cell formation. (2021)
  • Author(s): Leerach N, Munesue S, Harashima A, Kimura K, Oshima Y, Kawano S, Tanaka M, Niimura A, Sakulsak N, Yamamoto H, Hori O, Yamamoto Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 555 Pages: 74-80
  • DOI: 10.1016/j.bbrc.2021.03.139
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide‐induced microglial and astrocytic neuroinflammation by increasing NAD+ (2021)
  • Author(s): Roboon Jureepon、Hattori Tsuyoshi、Ishii Hiroshi、Takarada‐Iemata Mika、Nguyen Dinh Thi、Heer Collin D.、O'Meally Denis、Brenner Charles、Yamamoto Yasuhiko、Okamoto Hiroshi、Higashida Haruhiro、Hori Osamu
  • Journal Title: Journal of Neurochemistry Volume: 158 Issue: 2 Pages: 311-327
  • DOI: 10.1111/jnc.15367
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Venestatin from parasitic helminths interferes with receptor for advanced glycation end products (RAGE)-mediated immune responses to promote larval migration (2021)
  • Author(s): Tsubokawa Daigo、Kikuchi Taisei、Lee Jae Man、Kusakabe Takahiro、Yamamoto Yasuhiko、Maruyama Haruhiko
  • Journal Title: PLOS Pathogens Volume: 17 Issue: 6 Pages: e1009649-e1009649
  • DOI: 10.1371/journal.ppat.1009649
  • Peer Reviewed / Open Access
• [Journal Article] An improved sample extraction method reveals that plasma receptor for advanced glycation end-products (RAGE) modulates circulating free oxytocin in mice (2021)
  • Author(s): Cherepanov Stanislav M.、Gerasimenko Maria、Yuhi Teruko、Shabalova Anna、Zhu Hong、Yokoyama Shigeru、Salmina Alla B.、Munesue Shei-ichi、Harashima Ai、Yamamoto Yasuhiko、Higashida Haruhiro
  • Journal Title: Peptides Volume: 146 Pages: 170649-170649
  • DOI: 10.1016/j.peptides.2021.170649
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior (2020)
  • Author(s): Leerach Nontaphat、Harashima Ai、Munesue Seiichi、Kimura Kumi、Oshima Yu、Goto Hisanori、Yamamoto Hiroshi、Higashida Haruhiro、Yamamoto Yasuhiko
  • Journal Title: Glycoconjugate Journal Volume: in press Issue: 3 Pages: 303-310
  • DOI: 10.1007/s10719-020-09956-6
  • Peer Reviewed / Int'l Joint Research
• [Presentation] グリケーションからみる最新血管生物学 (2022)
  • Author(s): 原島 愛、山本靖彦
  • Organizer: 第95回日本生化学会大会
  • Invited
• [Presentation] 老化に関わる糖化研究から愛情のサイエンスへの展開 (2022)
  • Author(s): 山本靖彦
  • Organizer: 分子病理学会
  • Invited
• [Presentation] 糖化と全身疾患について-グリケーション研究の最前線 (2022)
  • Author(s): 山本靖彦
  • Organizer: 第22回日本抗加齢学会総会
  • Invited
• [Presentation] Glycation reaction and the receptor for advanced glycation end-products (RAGE): foe or friend for life? (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: 22nd IUNS-ICN
  • Int'l Joint Research / Invited
• [Presentation] 『転ばぬ先の知恵』全身疾患に関わる知恵 (2022)
  • Author(s): 山本靖彦
  • Organizer: 第127回日本眼科学会総会
  • Invited
• [Presentation] Understanding glycation and RAGE in diabetes and beyond (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: 4th MHRC Symposium at SIMS
  • Int'l Joint Research / Invited
• [Presentation] Oxytocin, RAGE and maternal bonding (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: The International Conference Social Brain-Focus on Emotions
  • Int'l Joint Research / Invited
• [Presentation] グリケーションとその最終産物受容体RAGE：病態形成における意義について (2021)
  • Author(s): 棟居聖一、山本靖彦
  • Organizer: 第94回日本生化学会シンポジウム
  • Invited
• [Remarks] 金沢大学大学院医薬保健学総合研究科医学専攻血管分子生物学HP
  • URL: https://biochem2.w3.kanazawa-u.ac.jp/