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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7714394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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