Background

CD137 signaling is an essential factor in cell fate and atherosclerosis. An increase in the number of apoptotic macrophages accelerates atherosclerotic development involving mitochondrial dynamics.However, the role of CD137 signaling in macrophage apoptosis and changes in mitochondria has not been demonstrated clearly.

Methods and Results

Here, we used ApoE^−/− mice as a model of atherosclerotic plaques. Mouse agonist anti-CD137 L and inhibitory anti-CD137 antibody were used to activate or block the CD137 signaling, respectively. Treatment of ApoE^−/− mice with agonist anti-CD137 L promoted the formation of necrotic cores and macrophage apoptosis in plaques. Further, activation of CD137 signaling caused macrophage apoptosis in vitro, with upregulation of caspase-9 and caspase-3 expression and an increase in the Bax/Bcl-2 ratio. Meanwhile, CD137 signaling promoted mitochondrial fission observed by mitochondrial fragmentation. Interestingly, inhibition of mitochondrial dynamin-related protein 1 (Drp1) using Mdivi-1 reduced the expression of pro-apoptotic proteins and the amounts of apoptotic macrophages induced by CD137 signaling. Finally, we also found that the p38 MAPK pathway activated by CD137 signaling increased the expression of Drp1 expression and number of mitochondrial fragmented structures. Inhibition of the p38 MAPK pathway by SB203580 attenuated mitochondrial dysfunction through reducing mitochondrial membrane potential loss, cytochrome c release, and mitochondrial reactive oxygen species (ROS) generation.

Conclusions

Overall, we identify a novel mechanism whereby CD137 signaling induces macrophage apoptosis through promoting mitochondrial fission dependent on the p38 MAPK pathway.

中文翻译：

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CD137信号激活促进巨噬细胞凋亡依赖于p38 MAPK通路介导的线粒体裂变

背景

CD137 信号传导是细胞命运和动脉粥样硬化的重要因素。凋亡巨噬细胞数量的增加加速了涉及线粒体动力学的动脉粥样硬化发展。然而，CD137 信号在巨噬细胞凋亡和线粒体变化中的作用尚未得到明确证明。

方法和结果

在这里，我们使用 ApoE ^-/-小鼠作为动脉粥样硬化斑块的模型。小鼠激动剂抗 CD137 L 和抑制性抗 CD137 抗体分别用于激活或阻断 CD137 信号传导。ApoE 的治疗^-/-具有激动剂抗 CD137 L 的小鼠促进了斑块中坏死核心的形成和巨噬细胞凋亡。此外，CD137 信号的激活导致体外巨噬细胞凋亡，caspase-9 和 caspase-3 表达上调，Bax/Bcl-2 比率增加。同时，CD137 信号促进了线粒体分裂观察到的线粒体裂变。有趣的是，使用 Mdivi-1 抑制线粒体动力蛋白相关蛋白 1 (Drp1) 降低了促凋亡蛋白的表达和 CD137 信号诱导的凋亡巨噬细胞的数量。最后，我们还发现由 CD137 信号激活的 p38 MAPK 通路增加了 Drp1 的表达和线粒体碎片结构的数量。

结论

总体而言，我们确定了一种新机制，即 CD137 信号通过促进依赖于 p38 MAPK 途径的线粒体裂变来诱导巨噬细胞凋亡。