TY - JOUR
T1 - 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
AU - Tenshin, Hirofumi
AU - Teramachi, Jumpei
AU - Ashtar, Mohannad
AU - Hiasa, Masahiro
AU - Inoue, Yusuke
AU - Oda, Asuka
AU - Tanimoto, Kotaro
AU - Shimizu, So
AU - Higa, Yoshiki
AU - Harada, Takeshi
AU - Oura, Masahiro
AU - Sogabe, Kimiko
AU - Hara, Tomoyo
AU - Sumitani, Ryohei
AU - Maruhashi, Tomoko
AU - Sebe, Mayu
AU - Tsutsumi, Rie
AU - Sakaue, Hiroshi
AU - Endo, Itsuro
AU - Matsumoto, Toshio
AU - Tanaka, Eiji
AU - Abe, Masahiro
N1 - Funding Information:
Masahiro Abe received research funding from Chugai Pharmaceutical, Sanofi KK, Pfizer Seiyaku KK, Kyowa Hakko Kirin, MSD KK, Astellas Pharma, Takeda Pharmaceutical, Teijin Pharma and Ono Pharmaceutical, and honoraria from the Daiichi Sankyo Company. The other authors declare no competing financial interests.
Funding Information:
This work was supported in part by the JSPS KAKENHI Grant Numbers JP18K08329, JP16K11504, JP17H05104, JP17KK0169, JP18H06294, JP19K21382, 19K22719, 19K08839, 20K18784 and 21H03111 and the Research Clusters Program of the Tokushima University. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
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U2 - 10.1002/cti2.1371
DO - 10.1002/cti2.1371
M3 - Article
AN - SCOPUS:85123517514
VL - 11
JO - Clinical and Translational Immunology
JF - Clinical and Translational Immunology
SN - 2050-0068
IS - 1
M1 - e1371
ER -