Investigation on pathological implications of guidance molecules in neuro-immune-metabolism.

• Project/Area Number: 18H05282
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Review Section: Broad Section I
• Research Institution: Osaka University
• Principal Investigator: 熊ノ郷 淳 大阪大学, 医学系研究科, 教授 (10294125)
• Co-Investigator(Kenkyū-buntansha): 奥野 龍禎 大阪大学, 医学系研究科, 准教授 (00464248)
• Project Period (FY): 2018-06-11 – 2023-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥192,140,000 (Direct Cost: ¥147,800,000、Indirect Cost: ¥44,340,000); Fiscal Year 2022: ¥37,700,000 (Direct Cost: ¥29,000,000、Indirect Cost: ¥8,700,000); Fiscal Year 2021: ¥37,700,000 (Direct Cost: ¥29,000,000、Indirect Cost: ¥8,700,000); Fiscal Year 2020: ¥37,700,000 (Direct Cost: ¥29,000,000、Indirect Cost: ¥8,700,000); Fiscal Year 2019: ¥37,700,000 (Direct Cost: ¥29,000,000、Indirect Cost: ¥8,700,000); Fiscal Year 2018: ¥41,340,000 (Direct Cost: ¥31,800,000、Indirect Cost: ¥9,540,000)
• Keywords: セマフォリン / 免疫代謝 / 神経・免疫・代謝 / ガイダンス因子 / 神経免疫クロストーく / 神経免疫クロストーク / 慢性炎症 / 神経ガイダンス因子 / 神経疾患 / 免疫疾患

Outline of Annual Research Achievements

自己免疫疾患を含む病的状態における免疫細胞の分化・活性化には細胞内の劇的な代謝シフトを伴うこと、これらの代謝変容は免疫応答に必須であることが相次いで報告され、「免疫代謝」として注目を集めている。例えば、炎症性マクロファージ分化時には好気的解糖が亢進するのに対し、抑制性マクロファージ分化時には酸化的リン酸化が亢進すること、これらの代謝シフトにおいて代謝センサーmTORが中心的役割を担うことなどが報告されていたが、マクロファージ分化時のmTORシグナルの詳細については不明な点が多い。申請者はこれまで、抑制性マクロファージ分化時にmTOR依存的に神経ガイダンス因子Sema6Dの発現が誘導されること、in vitroおよびin vivoのいずれにおいてもSema6D欠損により抑制性マクロファージ分化が阻害される一方で炎症性マクロファージへの分化が亢進することを発見し報告している。さらに細胞内の代謝シグナル解析から、Plexin-A4-Sema6DシグナルがSema6D細胞内領域へのc-Abl会合を介してPPARγの発現を誘導し、脂肪酸β酸化を亢進させていることを明らかにした。加えて、全身性の慢性炎症病態においては、骨髄内の交感神経の分布やその活性化が骨髄内の造血系の制御を介して炎症病態に関与しているとの知見も見出している.
本研究ではこれらの知見や研究背景の下、次年度においては、自己免疫疾患性制御を交感神経などの神経系制御の観点から検討するものである。特に免疫・炎症細胞分化に関わる細胞内代謝変化の解析については、Sema6D欠損マウスについては行動異常も観察されるため、神経生理学的な解析も行う。

Current Status of Research Progress

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

Reason

神経系と免疫系の代謝連関の中で、免疫疾患の病態解明や、治療につながる成果を目指すことを目的と掲げており、これまでの研究で論文発表を含め着実な成果が上がっているため。

Strategy for Future Research Activity

疾患モデル、患者検体を用いた解析、また、バイオインフォマティクス的な手法も取り入れて研究を進めていく予定である。

Assessment Rating

Interim Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, the expected progress has been made in research.

Research Products

• [Journal Article] Lipoid Pneumonia After Pembrolizumab Treatment for Advanced Non-Small-Cell Lung Cancer (2022)
  • Author(s): Yaga Moto、Shiroyama Takayuki、Hirata Haruhiko、Oya Kaori、Takeda Yoshito、Kumanogoh Atsushi
  • Journal Title: Clinical Lung Cancer Volume: 23
  • DOI: 10.1016/j.cllc.2021.12.003
  • Peer Reviewed / Open Access
• [Journal Article] Marked increase of interferon-β after BNT162b2 mRNA vaccination: a case of polyarthritis with pleurisy (2022)
  • Author(s): Shimagami Hiroshi、Yamaguchi Yuta、Kato Yasuhiro、Kumanogoh Atsushi
  • Journal Title: BMJ Case Reports Volume: 15
  • DOI: 10.1136/bcr-2021-246533
  • Peer Reviewed / Open Access
• [Journal Article] Rapid attenuation of anti-SARS-CoV-2 antibodies in patients with musculoskeletal diseases in whom intensive immunosuppressive therapies were reinitiated after COVID-19: comment on the article by Curtis et al (2022)
  • Author(s): Okamoto Masashi、Kawada Shoji、Shimagami Hiroshi、Fujii Naoko、Matsukawa Kazuki、Ishikawa Nachi、Kawamoto Keisuke、Higa Shinji、Ishida Yutaka、Ogata Atsushi、Yamaguchi Yuta、Morita Takayoshi、Kato Yasuhiro、Kumanogoh Atsushi
  • Journal Title: Arthritis & Rheumatology Volume: 74 Pages: 726-728
  • DOI: 10.1002/art.42003
  • Peer Reviewed / Open Access
• [Journal Article] Continuous Use of Etanercept During Pregnancy Does Not Affect TNF-Alpha Levels in Umbilical Cord Blood (2022)
  • Author(s): Nishide Masayuki、Yagita Mayu、Kumanogoh Atsushi
  • Journal Title: Biologics: Targets and Therapy Volume: Volume 16 Pages: 17-19
  • DOI: 10.2147/btt.s358449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crosstalk between axon guidance signaling and bone remodeling (2022)
  • Author(s): Nakanishi Yoshimitsu、Kang Sujin、Kumanogoh Atsushi
  • Journal Title: Bone Volume: 157 Pages: 116305-116305
  • DOI: 10.1016/j.bone.2021.116305
  • Peer Reviewed / Open Access
• [Journal Article] Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain (2022)
  • Author(s): Hasegawa Kana et al.
  • Journal Title: Science Transl. Med. Volume: 14 Pages: 7706-7706
  • DOI: 10.1126/scitranslmed.aax7706
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease (2021)
  • Author(s): Tomofuji Yoshihiko et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 81 Pages: 278-288
  • DOI: 10.1136/annrheumdis-2021-221267
  • Peer Reviewed / Open Access
• [Journal Article] Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese (2021)
  • Author(s): Tomofuji Yoshihiko、Maeda Yuichi、Oguro-Igashira Eri、Kishikawa Toshihiro、Yamamoto Kenichi、Sonehara Kyuto、Motooka Daisuke、Matsumoto Yuki、Matsuoka Hidetoshi、Yoshimura Maiko、Yagita Mayu、Nii Takuro、Ohshima Shiro、Nakamura Shota、Inohara Hidenori、Takeda Kiyoshi、Kumanogoh Atsushi、Okada Yukinori
  • Journal Title: Annals of the Rheumatic Diseases Volume: 80 Pages: 1575-1583
  • DOI: 10.1136/annrheumdis-2021-220687
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity (2021)
  • Author(s): Suga Y, Nagatomo I, Kinehara Y, Koyama S, Okuzaki D, Osa A, Naito Y, Takamatsu H, Nishide M, Nojima S, Ito D, Tsuda T, Nakatani T, Nakanishi Y, Futami Y, Koba T, Satoh S, Hosono Y, Miyake K, Fukushima K, Shiroyama T, Iwahori K, Hirata H, Takeda Y, Kumanogoh A.
  • Journal Title: The Journal of Immunology Volume: 207 Pages: 1456-1467
  • DOI: 10.4049/jimmunol.2100076
  • Peer Reviewed / Open Access
• [Journal Article] The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating myosin II (2021)
  • Author(s): Nakatani Takeshi、Tsujimoto Kohei、Park JeongHoon、Jo Tatsunori、Kimura Tetsuya、Hayama Yoshitomo、Konaka Hachiro、Morita Takayoshi、Kato Yasuhiro、Nishide Masayuki、Koyama Shyohei、Nada Shigeyuki、Okada Masato、Takamatsu Hyota、Kumanogoh Atsushi
  • Journal Title: Nature Communications Volume: 12 Pages: 23654-3
  • DOI: 10.1038/s41467-021-23654-3
  • Peer Reviewed / Open Access
• [Journal Article] Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes (2021)
  • Author(s): Kishikawa Toshihiro、Arase Noriko、Tsuji Shigeyoshi、Maeda Yuichi、Nii Takuro、Hirata Jun、Suzuki Ken、Yamamoto Kenichi、Masuda Tatsuo、Ogawa Kotaro、Ohshima Shiro、Inohara Hidenori、Kumanogoh Atsushi、Fujimoto Manabu、Okada Yukinori
  • Journal Title: Journal of dermatological science Volume: 102 Pages: 78-84
  • DOI: 10.1016/j.jdermsci.2021.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres. (2021)
  • Author(s): Koba, Takeda, Narumi, Shiromizu, Nojima, Ito, Kuroyama, Futami, Takimoto, Matsuki, Edahiro, Nojima, Hayama, Fukushima, Hirata, Koyama, Iwahori, Nagatomo, Suzuki, Shirai, Murakami, Nakanishi, Nakatani, Suga, Miyake, Shiroyama, Kida, Sasaki, Ueda, Mizuguchi, Adachi, Tomonaga, Kumanogoh
  • Journal Title: ERJ Open Research Volume: 7(1) Pages: 00658-2020
  • DOI: 10.1183/23120541.00658-2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predicting recurrence of respiratory failure in critically ill patients with COVID-19: A preliminary study (2021)
  • Author(s): Adachi Yuichi、Shiroyama Takayuki、Yamaguchi Yuta、Murakami Teruaki、Hirata Haruhiko、Amiya Saori、Niitsu Takayuki、Noda Yoshimi、Hara Reina、Enomoto Takatoshi、Morita Takayoshi、Kato Yasuhiro、Uchiyama Akinori、Takeda Yoshito、Kumanogoh Atsushi
  • Journal Title: Journal of Infection Volume: 82
  • DOI: 10.1016/j.jinf.2021.01.016
  • Peer Reviewed / Open Access
• [Journal Article] Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis (2021)
  • Author(s): Zhu Mingrui、Huang Yi、Bender Matthew E.、Girard Luc、Kollipara Rahul、Eglenen-Polat Buse、Naito Yujiro、Savage Trisha K.、Huffman Kenneth E.、Koyama Shohei、Kumanogoh Atsushi、Minna John D.、Johnson Jane E.、Akbay Esra A.
  • Journal Title: Cancer Research Volume: 81 Pages: 1813-1826
  • DOI: 10.1158/0008-5472.can-20-2808
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary metastases of lung adenocarcinoma mimicking COVID-19 pneumonia (2020)
  • Author(s): Shiroyama Takayuki、Hirata Haruhiko、Nagatomo Izumi、Takeda Yoshito、Kumanogoh Atsushi
  • Journal Title: Journal of Thoracic Disease Volume: 12 Pages: 6125-6126
  • DOI: 10.21037/jtd-20-2393
  • Peer Reviewed / Open Access
• [Journal Article] Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review (2020)
  • Author(s): Niitsu Takayuki、Shiroyama Takayuki、Miyake Kotaro、Noda Yoshimi、Kido Kansuke、Hara Reina、Enomoto Takatoshi、Adachi Yuichi、Amiya Saori、Suga Yasuhiko、Fukushima Kiyoharu、Koyama Shohei、Iwahori Kota、Hirata Haruhiko、Nagatomo Izumi、Takeda Yoshito、Kumanogoh Atsushi
  • Journal Title: Thoracic Cancer Volume: 11 Pages: 3625-3630
  • DOI: 10.1111/1759-7714.13716
  • Peer Reviewed / Open Access
• [Journal Article] Recovery from prolonged thrombocytopenia in patients with TAFRO syndrome: case series and literature review (2020)
  • Author(s): Yamaguchi Yuta、Maeda Yuichi、Shibahara Takayuki、Nameki Shinichiro、Nakabayashi Akihiko、Komuta Kiyohide、Mizuno Yumiko、Yagita Mayu、Manabe Yusuke、Morita Takayoshi、Nishide Masayuki、Watanabe Akane、Takamatsu Hyota、Nishida Sumiyuki、Hirano Toru、Shima Yoshihito、Narazaki Masashi、Kumanogoh Atsushi
  • Journal Title: Modern Rheumatology Case Reports Volume: 4 Pages: 302-309
  • DOI: 10.1080/24725625.2020.1717747
  • Peer Reviewed / Open Access
• [Journal Article] LRRK 2 regulates endoplasmic reticulum?mitochondrial tethering through the PERK ‐mediated ubiquitination pathway (2020)
  • Author(s): Toyofuku Toshihiko、Okamoto Yuki、Ishikawa Takako、Sasawatari Shigemi、Kumanogoh Atsushi
  • Journal Title: EMBO J. Volume: 39 Pages: 1-19
  • DOI: 10.15252/embj.2018100875
  • Peer Reviewed
• [Journal Article] Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis (2020)
  • Author(s): Tsuda Takeshi et al.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 145
  • Peer Reviewed / Open Access
• [Journal Article] Anti-receptor activator of nuclear factor κB ligand antibody treatment increases osteoclastogenesis-promoting IL-8 in patients with rheumatoid arthritis (2019)
  • Author(s): Morita Takayoshi、Shima Yoshihito、Fujimoto Kosuke、Tsuboi Hideki、Saeki Yukihiko、Narazaki Masashi、Ogata Atsushi、Kumanogoh Atsushi
  • Journal Title: International Immunology Volume: 31 Pages: 277-285
  • DOI: 10.1093/intimm/dxz009
  • Peer Reviewed / Open Access
• [Journal Article] Apoptosis-derived membrane vesicles drive cGAS-STING pathway and enhance type-I IFN production in systemic lupus erythematosus. (2018)
  • Author(s): Kato Y, Park J, Takamatsu H (*Corresponding author), Konaka H, Aoki W, Aburaya S, Ueda M, Nishide M, Koyama S, Hayama Y, Kinehara Y, Hirano T, Shima Y, Narazaki M, Kumanogoh A
  • Journal Title: Annals of the Rheumatic Diseases Volume: 77 Pages: 1507-15
  • DOI: 10.1136/annrheumdis-2018-212988
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells (2018)
  • Author(s): Kinehara Y, Nagatomo I, Koyama S,（30名飛ばして）, Kida H, Kumanogoh A
  • Journal Title: JCI Insight Volume: 3
  • DOI: 10.1172/jci.insight.123093
  • Peer Reviewed / Open Access
• [Journal Article] Selecting suitable chemotherapies for PD-1/PD-L1 blockade to optimize the tumor immune microenvironment (2018)
  • Author(s): Koyama Shohei、Nagatomo Izumi、Kijima Takashi、Kumanogoh Atsushi
  • Journal Title: Oncotarget Volume: 9 Pages: 32552-32553
  • DOI: 10.18632/oncotarget.26028
  • Peer Reviewed / Open Access
• [Journal Article] The Direct Oblique Method (2018)
  • Author(s): Miyake Kotaro、Morimura Osamu、Inoue Takako、Yoshida Kenya、Nagatomo Izumi、Kijima Takashi、Kumanogoh Atsushi
  • Journal Title: Journal of Bronchology & Interventional Pulmonology Volume: 25 Pages: 305-314
  • DOI: 10.1097/lbr.0000000000000512
  • Peer Reviewed
• [Journal Article] Clinical implications of monitoring nivolumab immunokinetics in non?small cell lung cancer patients (2018)
  • Author(s): Osa A, Uenami T, Koyama S, （22名飛ばして）, Kida H, Akbay EA, Hammerman PS, Wong KK, Dranoff G, Mori M, Kijima T, Kumanogoh A
  • Journal Title: JCI Insight Volume: 3
  • DOI: 10.1172/jci.insight.59125
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization (2018)
  • Author(s): Kang Sujin、Nakanishi Yoshimitsu、Kioi Yoshiyuki、Okuzaki Daisuke、Kimura Tetsuya、Takamatsu Hyota、Koyama Shohei、Nojima Satoshi、Nishide Masayuki、Hayama Yoshitomo、Kinehara Yuhei、Kato Yasuhiro、Nakatani Takeshi、Shimogori Tomomi、Takagi Junichi、Toyofuku Toshihiko、Kumanogoh Atsushi
  • Journal Title: Nature Immunology Volume: 19 Pages: 561-570
  • DOI: 10.1038/s41590-018-0108-0
  • Peer Reviewed / Open Access