The role of tryptophan-metabolizing enzymes in demyelination diseases

• Project/Area Number: 18K15377
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Fujita Health University
• Principal Investigator: Kunisawa Kazuo 藤田医科大学, 保健学研究科, 助教 (60780773)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: IDO2 / 多発性硬化症 / PLP4e/- / 脱髄 / IDO / 運動機能 / 免疫異常 / 髄鞘 / トリプトファン代謝 / 脱髄性疾患 / ミクログリア

Outline of Final Research Achievements

Multiple sclerosis (MS) is an autoimmune disease characterized by immune-mediated inflammation, which attacks the myelin sheath. We previously found that Indoleamine 2,3-dioxygenase 2 (IDO2) expression is induced in demyelinating lesions of murine model of transgenic demyelinating disease, Plp4e/-. Here, we investigated the effects of IDO2 deletion in the Plp4e/- mice by using behavioral analysis (locomotor activity, rotarod, and hanging-wire test). IDO2 deletion significantly increased severity of demyelination in the Plp4e/- mice. Thus, these results suggest that IDO2 plays a major role and regulates the demyelination and remyelination process in Plp4e/- mice.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症は難治性・進行性の脱髄性疾患であるが、現在の治療は抗炎症薬等による対症療法に限られており、その発症機序解明とそれを基盤とする根本的な治療法確立は急務である。本研究では、PLP4e/-マウスとIDO2欠損マウスを掛合わせたダブルトランスジェニックマウスの行動解析を行うことで、IDO2の病態形成への関与およびそれに基づく新規治療薬開発をより促進的に遂行できる。また、IDO2はT細胞等の末梢免疫細胞の活性化にも関与し、腫瘍増殖に影響を与える。従って、IDO2の機能的役割や免疫細胞の活性化機構が明らかになれば、腫瘍等の他の疾患発症を抑制する機能性因子の発見にも貢献することが期待できる。

Research Products

• [Journal Article] Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma (2019)
  • Author(s): Yamasuge Wakana、Yamamoto Yasuko、Fujigaki Hidetsugu、Hoshi Masato、Nakamoto Kentaro、Kunisawa Kazuo、Mouri Akihiro、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3061-3067
  • DOI: 10.1111/cas.14179
  • Peer Reviewed / Open Access
• [Journal Article] Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues (2019)
  • Author(s): Yoshida Yukihiro、Fujigaki Hidetsugu、Kato Koichi、Yamazaki Kyoka、Fujigaki Suwako、Kunisawa Kazuo、Yamamoto Yasuko、Mouri Akihiro、Oda Akifumi、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10243-10243
  • DOI: 10.1038/s41598-019-46666-y
  • Peer Reviewed / Open Access
• [Journal Article] Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression (2019)
  • Author(s): Lu Qiaohui、Mouri Akihiro、Yang Yang、Kunisawa Kazuo、Teshigawara Tomoaki、Hirakawa Mami、Mori Yuko、Yamamoto Yasuko、Libo Zou、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Behavioural Brain Research Volume: 372 Pages: 112053-112053
  • DOI: 10.1016/j.bbr.2019.112053
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through the regulation of IL-6/stat3 signalling (2018)
  • Author(s): Yamamoto Yasuko、Yamasuge Wakana、Imai Shinjiro、Kunisawa Kazuo、Hoshi Masato、Fujigaki Hidetsugu、Mouri Akihiro、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15917-15917
  • DOI: 10.1038/s41598-018-34166-4
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability (2018)
  • Author(s): Kunisawa Kazuo、Shimizu Takeshi、Kushima Itaru、Aleksic Branko、Mori Daisuke、Osanai Yasuyuki、Kobayashi Kenta、Taylor Anna M.、Bhat Manzoor A.、Hayashi Akiko、Baba Hiroko、Ozaki Norio、Ikenaka Kazuhiro
  • Journal Title: Journal of Neurochemistry Volume: 147 Issue: 3 Pages: 395-408
  • DOI: 10.1111/jnc.14553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of tryptophan metabolism in major depressive disorder (2019)
  • Author(s): Kazuo Kunisawa, Akihiro Mouri, Aika Kosuge, Tsubasa Iida, Bolati Wulaer, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
  • Invited
• [Presentation] IDO1 regulates vulnerability to social defeat stress (2019)
  • Author(s): Kazuo Kunisawa, Akihiro Mouri, Aika Kosuge, Tsubasa Iida, Bolati Wulaer, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 第42回日本神経科学大会第62回日本神経化学大会合同年会
• [Presentation] Development of animal models and biomarker for depression focused on serotonergic systems (2019)
  • Author(s): Akihiro Mouri, Kazuo Kunisawa, Hidetsugu Fujigaki, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
  • Invited
• [Presentation] The deficit of quinolinic acid phosphoribosyltransferase induces hypolocomotion and cognitive impairment through impairment of dopaminergic neuronal function (2019)
  • Author(s): Moe Niijima, Akihiro Mouri, Tomoaki Teshigawara, Kazuo Kunisawa, Hisayoshi Kubota, Mami Hirakawa, Yuko Mori, Masato Hoshi, Yasuko Yamamoto, Toshitaka Nabeshima, Kuniaki Saito
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
• [Presentation] Deficiency of kynurenine 3-monooxygenase increases vulnerability to the PCP-induced behavioral abnormalities (2019)
  • Author(s): Hisayoshi Kubota, Akihiro Mouri, Kazuo Kunisawa, Moe Niijima, Mami Hirakawa, Yuko Mori, Yasuko Yamamoto, Toshitaka Nabeshima, Kuniaki Saito
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
• [Presentation] Lipopolysaccharide injection triggers Indoleamine-2,3-dioxygenase1 and miR-874-3p interaction which leads to depression-like behavior in mouse (2019)
  • Author(s): Willy Jaya Suento, Kazuo Kunisawa, Bolati Wulaer, Tsubasa Iida, Aika Kosuge, Akihiro Mouri, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
• [Presentation] Impaired neurogenesis in the dentate gyrus of adult ShatiKO mice (2019)
  • Author(s): Bolati Wulaer, Kazuo Kunisawa, Willy Jaya Suent, Tsubasa Iida, Aika Kosuge, Atsumi Nitta, Akihiro Mouri, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP)
• [Presentation] IDO1 regulates vulnerability to social defeat stress (2019)
  • Author(s): Kazuo Kunisawa, Akihiro Mouri, Aika Kosuge, Tsubasa Iida, Bolati Wulaer, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: AsCNP-ASEAN 2019 Congress
  • Int'l Joint Research
• [Presentation] Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability (2018)
  • Author(s): Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Yasuyuki Osanai, Kenta Kobayashi, Anna M. Taylor, Manzoor A. Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki and Kazuhiro Ikenaka.
  • Organizer: 第23回グリア研究会
• [Presentation] うつ病発症におけるトリプトファン代謝の関与 (2018)
  • Author(s): 國澤 和生、毛利 彰宏、山本 康子、齋藤 邦明、鍋島 俊隆
  • Organizer: 第34回日本ストレス学会学術総会
• [Presentation] Repeated social defeat induces social interaction deficits associated with the alteration of kynurenine pathway activity in the prefrontal cortex (2018)
  • Author(s): Kazuo Kunisawa, Akihiro Mouri, Aika Kosuge, Tsubasa Iida, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research