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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

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...

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Autores principales: Tenshin, Hirofumi, Teramachi, Jumpei, Ashtar, Mohannad, Hiasa, Masahiro, Inoue, Yusuke, Oda, Asuka, Tanimoto, Kotaro, Shimizu, So, Higa, Yoshiki, Harada, Takeshi, Oura, Masahiro, Sogabe, Kimiko, Hara, Tomoyo, Sumitani, Ryohei, Maruhashi, Tomoko, Sebe, Mayu, Tsutsumi, Rie, Sakaue, Hiroshi, Endo, Itsuro, Matsumoto, Toshio, Tanaka, Eiji, Abe, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770968/
https://www.ncbi.nlm.nih.gov/pubmed/35079379
http://dx.doi.org/10.1002/cti2.1371
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author Tenshin, Hirofumi
Teramachi, Jumpei
Ashtar, Mohannad
Hiasa, Masahiro
Inoue, Yusuke
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Hara, Tomoyo
Sumitani, Ryohei
Maruhashi, Tomoko
Sebe, Mayu
Tsutsumi, Rie
Sakaue, Hiroshi
Endo, Itsuro
Matsumoto, Toshio
Tanaka, Eiji
Abe, Masahiro
author_facet Tenshin, Hirofumi
Teramachi, Jumpei
Ashtar, Mohannad
Hiasa, Masahiro
Inoue, Yusuke
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Hara, Tomoyo
Sumitani, Ryohei
Maruhashi, Tomoko
Sebe, Mayu
Tsutsumi, Rie
Sakaue, Hiroshi
Endo, Itsuro
Matsumoto, Toshio
Tanaka, Eiji
Abe, Masahiro
author_sort Tenshin, Hirofumi
collection PubMed
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.
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spelling pubmed-87709682022-01-24 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 Tenshin, Hirofumi Teramachi, Jumpei Ashtar, Mohannad Hiasa, Masahiro Inoue, Yusuke Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Hara, Tomoyo Sumitani, Ryohei Maruhashi, Tomoko Sebe, Mayu Tsutsumi, Rie Sakaue, Hiroshi Endo, Itsuro Matsumoto, Toshio Tanaka, Eiji Abe, Masahiro Clin Transl Immunology Original Articles 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. John Wiley and Sons Inc. 2022-01-19 /pmc/articles/PMC8770968/ /pubmed/35079379 http://dx.doi.org/10.1002/cti2.1371 Text en © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Tenshin, Hirofumi
Teramachi, Jumpei
Ashtar, Mohannad
Hiasa, Masahiro
Inoue, Yusuke
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Hara, Tomoyo
Sumitani, Ryohei
Maruhashi, Tomoko
Sebe, Mayu
Tsutsumi, Rie
Sakaue, Hiroshi
Endo, Itsuro
Matsumoto, Toshio
Tanaka, Eiji
Abe, Masahiro
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770968/
https://www.ncbi.nlm.nih.gov/pubmed/35079379
http://dx.doi.org/10.1002/cti2.1371
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