BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages.
BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages.
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作者：
Li J;Zhang L;Zheng Y;Shao R;Liang Q;Yu W;Wang H;Zou W;Wang D;Xiang J;Lin A
滑膜下层巨噬细胞对凋亡的抵抗在类风湿关节炎（RA）的关节炎症和破坏中起着至关重要的作用。然而，其潜在机制尚未完全了解。在这里，我们报告说，失活的促凋亡BCL-2家族蛋白BAD是必不可少的生存滑膜下层巨噬细胞在类风湿关节炎。在胶原诱导的关节炎（CIA）和TNFα转基因（TNF-Tg）小鼠模型中，Bad的遗传破坏导致更严重的关节炎症以及软骨和骨损伤，同时滑膜下层巨噬细胞凋亡减少。相反，Bad 3SA/3SA小鼠，其中BAD不能再被磷酸化灭活，被保护免于胶原诱导的关节炎。从机制上讲，磷酸化介导的BAD失活特异性地保护CIA和TNF-Tg小鼠以及RA患者关节炎关节高度炎症环境中的滑膜下层巨噬细胞免于凋亡，从而促进RA病理。我们的研究结果提出了一个模型，其中BAD的失活赋予滑膜下层巨噬细胞凋亡抵抗，从而有助于关节炎的发展，这表明BAD可能是RA的潜在治疗靶点。
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.