Study of osteo-nociceptive-immune system

• Project/Area Number: 15H05686
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Functional basic dentistry
• Research Institution: Osaka University
• Principal Investigator: Maruyama Kenta 大阪大学, 免疫学フロンティア研究センター, 特任助教(常勤) (60724119)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000); Fiscal Year 2017: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2016: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2015: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 骨代謝 / 真菌感染 / 痛覚 / 炎症 / 骨髄炎 / 真菌細胞壁 / 急性疼痛 / アロディニア / ATP / 疼痛 / 感染

Outline of Final Research Achievements

It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the β-glucan receptor Dectin-1 to induce CGRP. This induction of CGRP is independent of Bcl-10 or Malt-1 but dependent on TRPV1/TRPA1 ion channels. Hind paw β-glucan injection after Nav1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteo-inflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed β-glucan-induced inflammation and osteoclast multinucleation via direct suppression of NF-κB p65 by the transcriptional repressor Jdp2 and inhibition of actin polymerization, respectively. These findings clearly suggest the role of Dectin-1-mediated sensocrine pathways in the resolution of fungal osteo-inflammation.

Research Products

• [Int'l Joint Research] モナコ大学ARMI(オーストラリア)
• [Int'l Joint Research]
• [Int'l Joint Research] ＭＯＮＡＳＨ Ｕｎｉｖｅｒｓｉｔｙ/ＡＲＭＩ(オーストラリア)
• [Journal Article] Antitumor effect of Batf2 through IL-12 p40 up-regulation in tumor-associated macrophages. (2017)
  • Author(s): Kanemaru H, Yamane F, Fukushima K, Matsuki T, Kawasaki T, Ebina I, Kuniyoshi K, Tanaka H, Maruyama K, Maeda K, Satoh T, Akira S.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 35
  • DOI: 10.1073/pnas.1708598114
  • Peer Reviewed / Open Access
• [Journal Article] Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis (2017)
  • Author(s): Maruyama Kenta、Takayama Yasunori、Kondo Takeshi、Ishibashi Ken-ichi、Sahoo Bikash Ranjan、Kanemaru Hisashi、Kumagai Yutaro、Martino Mika?l M.、Tanaka Hiroki、Ohno Naohito、Iwakura Yoichiro、Takemura Naoki、Tominaga Makoto、Akira Shizuo
  • Journal Title: Cell Reports Volume: 19 Issue: 13 Pages: 2730-2742
  • DOI: 10.1016/j.celrep.2017.06.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasmodium products persist in the bone marrow and promote chronic bone loss (2017)
  • Author(s): Lee MSJ, Maruyama K, Fujita Y, Konishi A, Lelliott PM, Itagaki S, Horii T, Lin JW, Khan SM, Kuroda E, Akira S, Ishii KJ, Coban C.
  • Journal Title: Science Immunology Volume: 2 Issue: 12 Pages: 2-2
  • DOI: 10.1126/sciimmunol.aam8093
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanistic and structual basis of bioengineered bovine Cathelicidin-5 with optimized therapeutic activity (2017)
  • Author(s): Bikash R. Sahoo, Kenta Maruyama, Jyotheeswara R. Edula, Takahiro Tougan, Yuxi Lin, Young-Ho Lee, Toshihiro Horii, and Toshimichi Fujiwara
  • Journal Title: Scientific Reports Volume: 7:44781 Issue: 1 Pages: 44781-44796
  • DOI: 10.1038/srep44781
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Netrins as Prophylactic Targets of Skeletal diseases: A Double-Edged Sword? (2017)
  • Author(s): *Kenta Maruyama, Naoki Takemura, Mikael M. Martino, Takeshi Kondo, and Shizuo Akira.
  • Journal Title: Pharmacological Research Volume: 122 Pages: 46-52
  • DOI: 10.1016/j.phrs.2017.05.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bone-protective Functions of Netrin 1 Protein (2016)
  • Author(s): Kenta Maruyama, Takahiko Kawasaki, Masahide Hamaguchi, Motomu Hashimoto, Moritoshi Furu, Hiromu Ito, Takao Fujii, Naoki Takemura, Thangaraj Karuppuchamy, Takeshi Kondo, Takumi Kawasaki, Masahiro Fukusaka, Takuma Misawa, Tatsuya Saitoh, Yutaka Suzuki, Mikael M Martino, Yutaro Kumagai, and Shizuo Akira
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 46 Pages: 23854-23868
  • DOI: 10.1074/jbc.m116.738518
  • Peer Reviewed
• [Journal Article] 5-azacytidine-induced protein 2 (AZI2) regulates bone mass by fine-tuning osteoclast survival. (2015)
  • Author(s): Maruyama K, Fukasaka M, Uematsu S, Takeuchi O, Kondo T, Saitoh T, Martino M, Akira S.
  • Journal Title: J Biol Chem Volume: 290 Issue: 15 Pages: 9377-9386
  • DOI: 10.1074/jbc.m114.631374
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular matrix-inspired growth factor delivery systems for bone regeneration. (2015)
  • Author(s): Mikael M. Marutino, Priscilla S. Briquez, Kenta Maruyama, and Jeffrey A. Hubbell
  • Journal Title: Advanced Drug Delivery Reviews Volume: 94 Pages: 41-54
  • DOI: 10.1016/j.addr.2015.04.007
  • Peer Reviewed
• [Journal Article] Emerging molecules in the interface between skeletal system and innate immunity. (2015)
  • Author(s): Kenta Maruyama* and Shizuo Akira* (*corresponding author)
  • Journal Title: Pharmacological Research Volume: 99 Pages: 223-228
  • DOI: 10.1016/j.phrs.2015.06.005
  • Peer Reviewed
• [Journal Article] Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion. (2015)
  • Author(s): Yukiko Kuroda, Kenta Maruyama, Hideki Fujii, Isamu Sugawara, Shigeru Ko, Hisataka Yasuda, Hidenori Matsui, and Koichi Matsuo
  • Journal Title: PLoS One Volume: 11 Issue: 1 Pages: e0146544-e0146544
  • DOI: 10.1371/journal.pone.0146544
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. (2015)
  • Author(s): Mikael M Martino, Kenta Maruyama, Scott Stanger, Takashi Satoh, Osamu Takeuchi, Ralph Muller, and Shizuo Akira
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11051-11051
  • DOI: 10.1038/ncomms11051
  • NAID: 120005743659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 真菌感染随伴症状とATP (2018)
  • Author(s): 丸山健太
  • Organizer: 第138回 日本薬学会 一般シンポジウム“次世代のプリン作動性化学伝達遮断薬の創成を目指して
  • Invited
• [Presentation] 革新的組織滞留型抗炎症骨保護ペプチド (2017)
  • Author(s): 丸山健太
  • Organizer: メディカルジャパン2017大阪
  • Place of Presentation: インテックス大阪、大阪
  • Year and Date: 2017-02-17
  • Invited
• [Presentation] 骨神経免疫トライアングル理論を基盤とした真菌感染随伴疼痛の発生機構ならびにその生物学的意義に関する一考察 (2017)
  • Author(s): 丸山健太
  • Organizer: 生理学研究所研究会 痛みの理解を目指した先端的アプローチ
  • Place of Presentation: 自然科学研究機構岡崎カンファレンスセンター、名古屋
  • Year and Date: 2017-01-30
• [Presentation] Dectin-1-stimulated Sensocrine Nociceptor Pathways Inhibit Fungal Osteo-inflammation (2017)
  • Author(s): Kenta Maruyama
  • Organizer: 第19回 武田科学振興財団生命科学シンポジウム
  • Place of Presentation: 武田薬品研修所、大阪
  • Year and Date: 2017-01-20
• [Presentation] 真菌感染随伴疼痛の生物学的意義とは？ (2017)
  • Author(s): 丸山健太
  • Organizer: 第59回 歯科基礎医学会学術大会アップデートシンポジウム
  • Invited
• [Presentation] New players in Osteo-innate-immune system and their unexpected roles; novel molecules for novel therapies (2016)
  • Author(s): Kenta Maruyama
  • Organizer: Monash University Special Seminar
  • Place of Presentation: Monash University, ARMI (Clayton, Australia)
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] 骨神経免疫トライアングル理論を基盤とした真菌感染症の再考 (2016)
  • Author(s): 丸山健太、石橋健一、大野尚仁
  • Organizer: 第60回日本医真菌学会総会・学術集会
  • Place of Presentation: 台東館、東京
  • Year and Date: 2016-10-01
• [Presentation] 革新的局所滞留型抗炎症性骨保護ペプチド (2016)
  • Author(s): 丸山健太
  • Organizer: 科学技術振興機構 大阪大学新技術説明会
  • Place of Presentation: JST東京本部別館1F、東京
  • Year and Date: 2016-07-21
  • Invited
• [Presentation] Novel prophylactic targets of osteoporosis and pain: from Neuro-osteological point of view (2016)
  • Author(s): Ｋｅｎｔａ Ｍａｒｕｙａｍａ
  • Organizer: 千里ライフサイエンス財団 SENRIの会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2016-01-13
  • Invited
• [Presentation] Identification of the osteoclast fusion inhibitor (2015)
  • Author(s): Ｋｅｎｔａ Ｍａｒｕｙａｍａ
  • Organizer: アステラス病態代謝研究会
  • Place of Presentation: 東京工業倶楽部
  • Year and Date: 2015-10-17
  • Invited
• [Presentation] New players in skeletal system and their unexpected roles: novel molecules for novel therapies (2015)
  • Author(s): Ｋｅｎｔａ Ｍａｒｕｙａｍａ
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 2015-06-25
  • Invited
• [Book] 実験医学 2017年12月号 Vol.35 No.19、「Type2サイトカインによる感覚神経の直接刺激が痒みを増悪させる」 (2017)
  • Author(s): 丸山健太
  • Total Pages: 137
  • Publisher: 羊土社
  • ISBN: 9784758125024
• [Remarks]
  • URL: http://researchmap.jp/read0133961/?lang=english
• [Remarks]
  • URL: http://researchmap.jp/read0133961/
• [Patent(Industrial Property Rights)] 真菌感染における宿主応答抑制剤 (2017)
  • Inventor(s): 丸山健太、森山芳則、野村政壽
  • Industrial Property Rights Holder: 丸山健太、森山芳則、野村政壽
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-134071
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 組織損傷治療剤 (2017)
  • Inventor(s): 丸山健太、マルティーノ ミカエル エム、審良静男
  • Industrial Property Rights Holder: 丸山健太、マルティーノ ミカエル エム、審良静男
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-02-24
• [Patent(Industrial Property Rights)] 組織損傷治療剤 (2016)
  • Inventor(s): 丸山健太、ミカエルマルティーノエム、審良静男
  • Industrial Property Rights Holder: 丸山健太、ミカエルマルティーノエム、審良静男
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-036869
  • Filing Date: 2016-03-16