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BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages

The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essenti...

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Autores principales: Li, Jie, Zhang, Liansheng, Zheng, Yongwei, Shao, Rui, Liang, Qianqian, Yu, Weida, Wang, Hongyan, Zou, Weiguo, Wang, Demin, Xiang, Jialing, Lin, Anning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714394/
https://www.ncbi.nlm.nih.gov/pubmed/33270017
http://dx.doi.org/10.7554/eLife.56309
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author Li, Jie
Zhang, Liansheng
Zheng, Yongwei
Shao, Rui
Liang, Qianqian
Yu, Weida
Wang, Hongyan
Zou, Weiguo
Wang, Demin
Xiang, Jialing
Lin, Anning
author_facet Li, Jie
Zhang, Liansheng
Zheng, Yongwei
Shao, Rui
Liang, Qianqian
Yu, Weida
Wang, Hongyan
Zou, Weiguo
Wang, Demin
Xiang, Jialing
Lin, Anning
author_sort Li, Jie
collection PubMed
description The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad(3SA/3SA) mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA.
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spelling pubmed-77143942020-12-07 BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages Li, Jie Zhang, Liansheng Zheng, Yongwei Shao, Rui Liang, Qianqian Yu, Weida Wang, Hongyan Zou, Weiguo Wang, Demin Xiang, Jialing Lin, Anning eLife Immunology and Inflammation The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad(3SA/3SA) mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA. eLife Sciences Publications, Ltd 2020-12-03 /pmc/articles/PMC7714394/ /pubmed/33270017 http://dx.doi.org/10.7554/eLife.56309 Text en © 2020, Li et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Li, Jie
Zhang, Liansheng
Zheng, Yongwei
Shao, Rui
Liang, Qianqian
Yu, Weida
Wang, Hongyan
Zou, Weiguo
Wang, Demin
Xiang, Jialing
Lin, Anning
BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title_full BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title_fullStr BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title_full_unstemmed BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title_short BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
title_sort bad inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714394/
https://www.ncbi.nlm.nih.gov/pubmed/33270017
http://dx.doi.org/10.7554/eLife.56309
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