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ID 117260
Title Alternative
LL-Z1640-2 for rheumatoid arthritis
Author
Ashtar, Mohannad Tokushima University
Inoue, Yusuke Tokushima University
Oda, Asuka Tokushima University
Tanimoto, Kotaro Tokushima University
Higa, Yoshiki Tokushima University
Oura, Masahiro Tokushima University
Maruhashi, Tomoko Tokushima University
Sebe, Mayu Tokushima University
Keywords
rheumatoid arthritis
NLRP3 inflammasome
TAK1
LL-Z1640-2
synovial fibroblasts
macrophage
osteoclast
Content Type
Journal Article
Description
Objectives: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF-β-activated kinase-1 (TAK1) inhibitor LL-Z1640-2 (LLZ) on joint inflammation and bone destruction in collagen-induced arthritis (CIA).
Methods: LL-Z1640-2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed.
Results: NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL-1β production. LLZ also suppressed LPS-induced production of TACE and TNF-α in bone marrow macrophages and abolished IL-1β-induced production of MMP-3, IL-6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL-mediated OC formation and activation.
Conclusion: TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA.
Journal Title
Clinical & Translational Immunology
ISSN
20500068
Publisher
Australian and New Zealand Society for Immunology|John Wiley & Sons
Volume
11
Issue
1
Start Page
e1371
Published Date
2022-01-19
Rights
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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language
eng
TextVersion
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departments
Oral Sciences
University Hospital
Medical Sciences
Institute of Advanced Medical Sciences