Elucidation and treatment of physiological phenomena and abnormalities of pregnancy based on macrophage balance

• Project/Area Number: 19K09823
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: University of Yamanashi (2021-2022); Kitasato University (2019-2020)
• Principal Investigator: YOSHINO OSAMU 山梨大学, 大学院総合研究部, 准教授 (00466757)
• Co-Investigator(Kenkyū-buntansha): 中島 彰俊 富山大学, 学術研究部医学系, 教授 (00436792)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: マクロファージ / 着床 / 子宮内膜症 / 血管新生 / IL-33 / S1P / 血管新生因子 / M1/M2型

Outline of Research at the Start

マクロファージのサブタイプである、M1,M2Mφの生殖領域における生理的現象および、その異常状態における分布およびその作用を、ヒトおよびマウス検体を用いて検討する。そしてM2MφからM1Mφ、もしくはM1MφからM2Mφへのシフトを誘導する薬剤を用いて、M1/M2Mφバランスの是正が不妊症、流・早産、子宮内膜症の新たな治療法になり得るかを明らかにする。

Outline of Final Research Achievements

Using an experimental system in which M2Mφ can be removed in vivo by administration of diphtheria toxin (DT), we found that M2Mφ is essential for embryo implantation and that M2Mφ contributes to implantation by regulating proinflammatory state by decreasing the WNT/beta catenin signaling pathway. In endometriosis, M2Mφ regulates angiogenesis, which leads to exacerbation of the disease. In addition, we found that M2Mφ is highly expressed in the endometrium in infertile women with M1>M2Mφ imbalance, resulting in a proinflammatory state and implantation failure, and that in endometriosis, M2Mφ is abundant in the lesions.

Academic Significance and Societal Importance of the Research Achievements

近年、子宮内膜炎と不妊症との関係が注目されているが、その病理学的メカニズムに関しては不明な点が多い。今回抗生剤による子宮内膜炎治療が、子宮内膜におけるM1、M2マクロファージバランスを整えることで胚着床に寄与する可能性を示すことができた。また、子宮内膜症においては、M2マクロファージが病態に対して増悪因子であることを明らかにすることができた。

Research Products

• [Journal Article] Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Has the Same Effect as Gonadotropin-Releasing Hormone Agonist Injections in Terms of Preparation for Transcervical Resection Myomectomy (2022)
  • Author(s): Yoshino Osamu、Ito Mika、Hiraoka Takehiro、Ono Yosuke、Tanaka Kouta、Iwahata Shunsuke、Honda Masako、Furue Akiko、Nishijima Junichi、Shimoda Takahito、Iwase Haruko、Miki Akinori、Tagaya Hikaru、Hirata Shuji、Unno Nobuya
  • Journal Title: Gynecology and Minimally Invasive Therapy Volume: 11 Issue: 4 Pages: 238-238
  • DOI: 10.4103/gmit.gmit_9_22
• [Journal Article] National survey of abnormal uterine bleeding according to the FIGO classification in Japan (2022)
  • Author(s): Kitahara Yoshikazu、Hiraike Osamu、Ishikawa Hiroshi、Kugu Koji、Takai Yasushi、Yoshino Osamu、Ono Masanori、Maekawa Ryo、Ota Ikuko、Iwase Akira
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 49 Issue: 1 Pages: 321-330
  • DOI: 10.1111/jog.15464
  • Peer Reviewed
• [Journal Article] Guidelines for Reproductive Medicine in Japan (2022)
  • Author(s): Yamada Mitsutoshi、Osuka Satoko、Kanasaki Haruhiko、Kawano Yasushi、Kawamura Kazuhiro、Kishi Hiroshi、Kimura Fuminori、Kuroda Shinnosuke、Kuwahara Akira、Tamura Hiroshi、Jwa Seung Chik、Baba Tsuyoshi、Harada Miyuki、Hirata Tetsuya、Yoshino Osamu、Hirota Yasushi、Tsujimura Akira、Kuji Naoaki、Osuga Yutaka
  • Journal Title: Reproductive Medicine and Biology Volume: 21 Issue: 1 Pages: 1-1
  • DOI: 10.1002/rmb2.12483
  • Peer Reviewed / Open Access
• [Journal Article] CD206+?macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model (2021)
  • Author(s): Ono Yosuke、Yoshino Osamu、Hiraoka Takehiro、Sato Erina、Furue Akiko、Nawaz Allah、Hatta Hideki、Fukushi Yoshiyuki、Wada Shinichiro、Tobe Kazuyuki、Hirota Yasushi、Osuga Yutaka、Unno Nobuya、Saito Shigeru
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 853-853
  • DOI: 10.1038/s41598-020-79578-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis. (2021)
  • Author(s): Ono Y., Kawakita T., Yoshino O., Sato E., Kano K., Ohba M., Okuno T., Ito M., Koga K., Honda M., Furue A., Hiraoka T., Wada S., Iwasa T., Yokomizo T., Aoki J., Maeda N., Unno N., Osuga Y., Hirata S.
  • Journal Title: Biomedicines Volume: 9(11) Issue: 11 Pages: 1519-1519
  • DOI: 10.3390/biomedicines9111519
  • Peer Reviewed / Open Access
• [Journal Article] Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition (2021)
  • Author(s): Kawaguchi R, Matsumoto K, Ishikawa T, Ishitani K, Okagaki R, Ogawa M, Oki T, Ozawa N, Kawasaki K, Kuwabara Y, Koga K, Sato Y, Takai Y, Tanaka K, Tanebe K, Terauchi M, Todo Y, Nose-Ogura S, Noda T, Baba T, Fujii E, Fujii T, Miyazaki H, Yoshino O, Yoshimura K, Maeda T, Kudo Y, Kobayashi H.
  • Journal Title: The Journal of Obstetrics and Gynecology Research Volume: 47 Issue: 1 Pages: 5-25
  • DOI: 10.1111/jog.14487
  • Peer Reviewed
• [Journal Article] Perinatal outcomes associated with the positional relationship between the placenta and the adenomyosis lesion (2021)
  • Author(s): Ono Yosuke、Ota Hajime、Takimoto Kanako、Tsuzuki Yoko、Nakajima Ayako、Yoshino Osamu、Unno Nobuya、Fujino Takafumi、Fukushi Yoshiyuki、Wada Shinichiro
  • Journal Title: Journal of Gynecology Obstetrics and Human Reproduction Volume: 50 Issue: 7 Pages: 102114-102114
  • DOI: 10.1016/j.jogoh.2021.102114
  • Peer Reviewed
• [Journal Article] Bone morphogenetic protein‐2 enhances gonadotropin‐independent follicular development via sphingosine kinase 1 (2020)
  • Author(s): Ito Masami、Yoshino Osamu、Ono Yosuke、Yamaki‐Ushijima Akemi、Tanaka Tomoko、Shima Tomoko、Orisaka Makoto、Iwase Akira、Nakashima Akitoshi、Saito Shigeru
  • Journal Title: American Journal of Reproductive Immunology Volume: 85 Issue: 5
  • DOI: 10.1111/aji.13374
  • Peer Reviewed / Open Access
• [Journal Article] CD206+ M2-like Macrophages are Essential for Successful Implantation. (2020)
  • Author(s): Ono Y, Yoshino O, Ushijima A, Hiraoka T, Fukui Y, Nawaz A, Hirota Y, Wada S, Tobe K, Nakashima A, Osuga Y and Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 557184-557184
  • DOI: 10.3389/fimmu.2020.557184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation (2020)
  • Author(s): Yoshino Osamu、Ono Yosuke、Honda Masako、Hattori Kyoko、Sato Erina、Hiraoka Takehiro、Ito Masami、Kobayashi Mutsumi、Arai Kenta、Katayama Hidekazu、Tsuchida Hiroyoshi、Yamada-Nomoto Kaori、Iwahata Shunsuke、Fukushi Yoshiyuki、Wada Shinichiro、Iwase Haruko、Koga Kaori、Osuga Yutaka、Iwaoka Michio、Unno Nobuya
  • Journal Title: Biomedicines Volume: 8 Issue: 11 Pages: 467-467
  • DOI: 10.3390/biomedicines8110467
  • Peer Reviewed
• [Journal Article] Inhibition of autophagy in theca cells induces CYP17A1 and PAI-1 expression via ROS/p38 and JNK signalling during the development of polycystic ovary syndrome (2020)
  • Author(s): Kobayashi Mutsumi、Yoshino Osamu、Nakashima Akitoshi、Ito Masami、Nishio Kazuyuki、Ono Yosuke、Kusabiraki Tae、Kunitomi Chisato、Takahashi Nozomi、Harada Miyuki、Hattori Katsushige、Orisaka Makoto、Osuga Yutaka、Saito Shigeru
  • Journal Title: Molecular and Cellular Endocrinology Volume: 15 Pages: 110792-110792
  • DOI: 10.1016/j.mce.2020.110792
  • Peer Reviewed
• [Journal Article] Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment (2020)
  • Author(s): Hiraoka Takehiro、Hirota Yasushi、Fukui Yamato、Gebril Mona、Kaku Tetsuaki、Aikawa Shizu、Hirata Tomoyuki、Akaeda Shun、Matsuo Mitsunori、Haraguchi Hirofumi、Saito-Kanatani Mayuko、Shimizu-Hirota Ryoko、Takeda Norihiko、Yoshino Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15523-15523
  • DOI: 10.1038/s41598-020-72640-0
  • Peer Reviewed / Open Access
• [Journal Article] Uterine CD11c+ cells induce the development of paternal antigen-specific Tregs via seminal plasma priming (2020)
  • Author(s): Shima Tomoko、Nakashima Akitoshi、Yasuda Ippei、Ushijima Akemi、Inada Kumiko、Tsuda Sayaka、Yoshino Osamu、Tomura Michio、Saito Shigeru
  • Journal Title: Journal of Reproductive Immunology Volume: - Pages: 103165-103165
  • DOI: 10.1016/j.jri.2020.103165
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sphingosine 1 Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells. (2019)
  • Author(s): Yoshino O, Yamada-Nomoto K, Kano K, Ono Y, Kobayashi M, Ito M, Yoneda S, Nakashima A, Shima T, Onda T, Osuga Y, Aoki J, Saito S.
  • Journal Title: Reprod Sci. Volume: 1933719119828112 Issue: 11 Pages: 1460-1467
  • DOI: 10.1177/1933719119828112
  • Peer Reviewed
• [Journal Article] Serum Brain-derived Neurotrophic Factor Levels Mirror Bone Mineral Density in Amenorrheic and Eumenorrheic Athletes. (2019)
  • Author(s): Nose S, Yoshino O, Nomoto K, Harada M, Dohi M, Kawahara T, Osuga Y, Fujii T, Saito S.
  • Journal Title: Int J Sports Med. Volume: 40(4) Issue: 04 Pages: 276-282
  • DOI: 10.1055/a-0835-6119
  • Peer Reviewed
• [Journal Article] Risk factors of stress fractures due to the female athlete triad: Differences in teens and twenties. (2019)
  • Author(s): Nose-Ogura S, Yoshino O, Dohi M, Kigawa M, Harada M, Hiraike O, Onda T, Osuga Y, Fujii T, Saito S.
  • Journal Title: Scand J Med Sci Sports. Volume: 29(10): Issue: 10 Pages: 1501-1510
  • DOI: 10.1111/sms.13464
  • Peer Reviewed
• [Journal Article] Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway (2019)
  • Author(s): Takeuchi Arisa、Koga Kaori、Satake Erina、Makabe Tomoko、Taguchi Ayumi、Miyashita Mariko、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Yoshino Osamu、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 104 Issue: 11 Pages: 5547-5554
  • DOI: 10.1210/jc.2019-00281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of Nerve Injury-Induced Protein1 (Ninj1) in Endometriosis (2018)
  • Author(s): Miyashita Mariko、Koga Kaori、Takeuchi Arisa、Makabe Tomoko、Taguchi Ayumi、Urata Yoko、Izumi Gentaro、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Wada-Hiraike Osamu、Yoshino Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Reproductive Sciences Volume: in press Issue: 8 Pages: 368-375
  • DOI: 10.1177/1933719118806395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 子宮内膜症性嚢胞の鑑別におけるMRI IDEAL IQの有用性についての検討 (2021)
  • Author(s): 古江 明子, 平岡 毅大, 本田 雅子, 岩端 俊輔, 吉野 修, 岩瀬 春子, 海野 信也
  • Organizer: 日本産科婦人科学会学術集会
• [Presentation] RAMP1受容体シグナルによる子宮内膜症進展制御機構 (2021)
  • Author(s): 本田 雅子, 伊藤 義也, 服部 響子, 関口 和企, 吉野 修, 岩瀬 春子, 海野 信也
  • Organizer: 日本産科婦人科学会学術集会
• [Presentation] 生殖内分泌学 基礎から臨床へ (2021)
  • Author(s): 吉野 修
  • Organizer: 関東連合産科婦人科学会
  • Invited
• [Presentation] 日本人月経困難症患者を対象としたQOL・労働生産性に関するePRO研究 (2021)
  • Author(s): 吉野 修, 高橋 法子, 鈴鴨 よしみ
  • Organizer: 日本女性医学学会
• [Presentation] From where the inflammation comes? (2019)
  • Author(s): O. Yoshino, Y. Ono, N. Unno, T. Onda, Y Osuga and S. Saito
  • Organizer: ISIR meeting 2019
  • Int'l Joint Research / Invited
• [Presentation] The involvement of Damage-associated molecular patterns (DAMPs) and macrophages in the etiology of endometriosis. (2019)
  • Author(s): Osamu Yoshino, Yosuke Ono, Nobuya Unno, Onda Takashi, Shigeru Saito and Yutaka Osuga
  • Organizer: ASRI meeting
  • Int'l Joint Research / Invited