Investigation of the role of TAK1-NLRP3 inflammasome axis in rheumatoid arthritis

• Project/Area Number: 20K18784
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57070:Developmental dentistry-related
• Research Institution: The University of Tokushima
• Principal Investigator: TENSHIN Hirofumi 徳島大学, 病院, 助教 (00829187)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己免疫性疾患 / 関節破壊 / NLRP3インフラマソーム / TAK1 / 破骨細胞 / 滑膜線維芽細胞 / 関節リウマチ / マクロファージ / 炎症

Outline of Research at the Start

関節リウマチ（RA）による炎症と骨破壊は依然既存薬では制御が困難な場合があり、新たな治療戦略の開発が要求されている。NLRP3インフラマソームは組織破壊や感染に対してIL-1βやIL-18を分泌する生体防御機構であるが、近年RAの進展や難治性にインフラマソームの過剰な形成の関与が示唆されている。しかし、その実態は依然不明なままである。本研究では、RAにおけるNLRP3インフラマソームを起点とした炎症および骨破壊の進展の機序を、TAK1に着目して解析を行うことで明らかにし、TAK1の活性（リン酸化）を標的とした炎症と骨破壊を同時に制御する新規治療法を開発することを目的とする。

Outline of Final Research Achievements

Aberrant activation of NLRP3 inflammasome, the protein complex to produce IL-1β, has been reported in various types of inflammatory diseases. But in rheumatoid arthritis, its contribution is still not clear. Thus, we explored the role of NLRP3 inflammasome in RA and treatment strategy against inflammasome activation.
Synovial macrophages in RA animal model expressed NLRP3 inflammasome and IL-1β expression in sera was upregulated. TAK1 inhibitor, LLZ1640-2 inhibited NLRP3 inflammasome in vitro and in vivo. LLZ1640-2 strongly suppressed joint inflammation and bone destruction by not only inhibited IL-1β expression, but also inhibited IL-1β-mediated signaling in synovial fibroblast. In addition, LLZ1640-2 directly inhibited RANKL-mediated OC differentiation.
These result suggest that TAK1 inhibition with LLZ1640-2 may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in rheumatoid arthritis.

Academic Significance and Societal Importance of the Research Achievements

近年、関節リウマチでは治療法の発展に伴い重度の関節破壊を抑制することが可能となってきているものの、既存薬が奏効しないケースもあり、未知の関節破壊誘導機序の存在が示唆されている。また、一度関節破壊が生じると運動障害によるQoLの低下を引き起こすため、病態の解明と新規治療戦略の開発は喫緊の課題と言える。今回の研究によって病態におけるインフラマソームの関与が明らかとなったことは、RAの発症・進展機序を明らかにしていく上で学術的意義が大きい。また、制御が困難であったインフラマソームをTAK1阻害剤が抑制することを見出したことは、今後の創薬にも繋がり得る研究成果であり社会的意義も大きい。

Research Products

• [Journal Article] Mechanical unloading aggravates bone destruction and tumor expansion in myeloma (2022)
  • Author(s): Tanimoto K, Hiasa M, Tenshin H, Teramachi J, Oda A, Harada T, Higa Y, Sogabe K, Oura M, Sumitani R, Hara T, Endo I, Matsumoto T, Tanaka E, Abe M
  • Journal Title: Haematologica Volume: 107 Issue: 3 Pages: 744-749
  • DOI: 10.3324/haematol.2021.278295
  • Peer Reviewed / Open Access
• [Journal Article] TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression (2022)
  • Author(s): Tenshin H, Teramachi J, Ashtar M, Hiasa M, Inoue Y, Oda A, Tanimoto K, Shimizu S, Higa Yi, Harada T, Oura M, Sogabe K, Hara T, Sumitani R, Maruhashi T, Sebe M, Tsutsumi R, Sakaue H, Endo I, Matsumoto T, Tanaka E, Abe M
  • Journal Title: Clinical & Translational Immunology Volume: 11 Issue: 1
  • DOI: 10.1002/cti2.1371
  • Peer Reviewed / Open Access
• [Journal Article] Reveromycin A, a novel acid-seeking agent, ameliorates bone destruction and tumor growth in multiple myeloma. (2020)
  • Author(s): Keiichiro Watanabe、Ariunzaya Bat-Erdene、Hirofumi Tenshin、Qu Cui、Jumpei Teramachi、Masahiro Hiasa、Asuka Oda、Takeshi Harada、Hirokazu Miki、Kimiko Sogabe、Masahiro Oura、Ryohei Sumitani、Yukari Mitsui、Itsuro Endo、Eiji Tanaka、Makoto Kawatani、Hiroyuki Osada、Toshio Matsumoto、Masahiro Abe
  • Journal Title: Haematologica Volume: 106 Issue: 4 Pages: 1172-1177
  • DOI: 10.3324/haematol.2019.244418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat. (2020)
  • Author(s): 1. Ashtar M, Tenshin H, Teramachi J, Bat-Erdene A, Hiasa M, Oda A, Tanimoto K, Shimizu S, Higa Y, Harada T, Oura M, Sogabe K, Nakamura S, Fujii S, Sumitani R, Miki H, Udaka K, Takahashi M, Kagawa K, Endo I, Tanaka E, Matsumoto T, Abe M.
  • Journal Title: Cancers (Basel) Volume: 12 Issue: 4 Pages: 929-929
  • DOI: 10.3390/cancers12040929
  • NAID: 120006894611
  • Peer Reviewed / Open Access
• [Presentation] Targeting SLAMF7 to disrupt myeloma-osteoclast interaction: elotuzumab’s ADCC activity with Th1-like γδT cells towards osteoclasts and myeloma cells. (2022)
  • Author(s): Hirofumi Tenshin, Takeshi Harada, Yusuke Inoue, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, So Shimizu, Yoshiki Higa, Emiko Nakaue, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka, Masahiro Abe
  • Organizer: Cancer and bone society young investigator symposium
  • Int'l Joint Research / Invited
• [Presentation] The anti-SLAMF7 elotuzumab enhances ADCC activity with Th1-like γδT cells towards osteoclasts and myeloma cells. (2021)
  • Author(s): Hirofumi Tenshin, Takeshi Harada, Yusuke Inoue, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Kotaro Tanimoto, So Shimizu, Yoshiki Higa, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Tomoko Maruhashi, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe
  • Organizer: The European Calcified Tissue Society 2021 Digital Congress
  • Int'l Joint Research
• [Presentation] 抗SLAMF7抗体エロツスマブはγδT細胞による破骨細胞および骨髄腫細胞へのADCC活性を増強する (2021)
  • Author(s): 天真 寛文, 原田 武志, 井上 雄介, 寺町 順平, 日浅 雅博, 谷本 幸多朗, 清水 宗, 比嘉 佳基, 大浦 雅博,曽我部 公子,中村 信元, 三木 浩和, 遠藤 逸朗, 田中 栄二, 松本 俊夫, 安倍 正博
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] The novel therapeutic approaches with TAK1 inhibition against the aberrant NLRP3 inflammasome activation in rheumatoid arthritis (2020)
  • Author(s): Hirofumi Tenshin, Mohannad Ashtar, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Kotaro Tanimoto, So Shimizu, Yoshiki Higa, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: ヨーロッパ骨代謝学会（ECTS）
  • Int'l Joint Research