TY - JOUR TI - BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages AU - Li, Jie AU - Zhang, Liansheng AU - Zheng, Yongwei AU - Shao, Rui AU - Liang, Qianqian AU - Yu, Weida AU - Wang, Hongyan AU - Zou, Weiguo AU - Wang, Demin AU - Xiang, Jialing AU - Lin, Anning A2 - Rath, Satyajit A2 - Rothlin, Carla V A2 - Tuckermann, Jan P A2 - Pope, Richard VL - 9 PY - 2020 DA - 2020/12/03 SP - e56309 C1 - eLife 2020;9:e56309 DO - 10.7554/eLife.56309 UR - https://doi.org/10.7554/eLife.56309 AB - 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, Bad3SA/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. KW - BAD KW - macrophages KW - rheumatoid arthritis KW - apoptosis KW - inflammation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -