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

2021 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

矯正歯科学

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。