Activated toll-like receptor 4 is involved in oridonin-induced phagocytosis via promotion of migration and autophagy-lysosome pathway in RAW264.7 macrophages.
Activated toll-like receptor 4 is involved in oridonin-induced phagocytosis via promotion of migration and autophagy-lysosome pathway in RAW264.7 macrophages.
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激活的 Toll 样受体 4 通过促进 RAW264.7 巨噬细胞的迁移和自噬-溶酶体途径参与冬凌草甲素诱导的吞噬作用。
DOI：
10.1016/j.intimp.2018.11.014
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发表时间：
2019
影响因子：
5.6
通讯作者：
Ikejima Takashi
中科院分区：
文献类型：
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作者：
Zang Linghe;Wang Jian;Ren Yanlin;Liu Weiwei;Yu Yang;Zhao Songyan;Otkur Wuxiyar;Zhao Yingxi;Hayashi Toshihiko;Tashiro Shin-Ichi;Onodera Satoshi;Ikejima Takashi
在我们以前的研究中，我们证明了冬凌草甲素通过诱导自噬增强巨噬细胞样细胞对凋亡小体的吞噬作用。然而，自噬的直接传感器和控制吞噬作用的关键事件仍然未知。在此，我们表明，Toll样受体4（TLR 4），已知介导的免疫反应，被激活的冬凌草甲素。活化的TLR 4有助于RAW264.7巨噬细胞吞噬凋亡细胞。事实上，抑制或小干扰RNA（siRNA）沉默TLR 4显着减弱冬凌草甲素诱导的吞噬作用。TLR 4的抑制也降低了自噬及其相关蛋白Beclin-1和轻链3（LC 3）的水平，表明活化的TLR 4参与自噬的活化。LPS诱导的TLR 4活化促进吞噬作用和自噬进展。TLR 4的激活伴随溶酶体酸性磷酸酶和组织蛋白酶B活性的增加以及溶酶体相关膜蛋白（LAMP 1和2）水平的上调。此外，与易位至细胞质相关的TLR 4通过增加骨架和/或膜结构的可塑性导致巨噬细胞运动或迁移。这些结果表明，冬凌草甲素诱导的巨噬细胞吞噬凋亡小体是TLR 4信号通路介导的，通过激活自噬-溶酶体途径以及增加细胞迁移。
In our previous study, we demonstrated that oridonin enhances phagocytosis of apoptotic bodies by macrophage-like cells by inducing autophagy. However, the direct sensor of autophagy and the key event controlling phagocytosis remains unknown. Herein, we showed that Toll-like receptor 4 (TLR4), known to mediate immune responses, was activated by oridonin. Activated TLR4 contributes to phagocytosis of apoptotic cells by RAW264.7 macrophages. Indeed, inhibition or small interfering RNA (siRNA) silencing of TLR4 significantly attenuated oridonin-induced phagocytosis. Inhibition of TLR4 also decreased the level of autophagy and its associated proteins, Beclin-1 and light chain 3 (LC3), suggesting that activated TLR4 is involved in activation of autophagy. LPS-induced activation of TLR4 promoted phagocytosis and autophagy progression. Activation of TLR4 accompany increase in activities of lysosome acid phosphatase and cathepsin B as well as in up-regulation of lysosomal-associated membrane protein (LAMP 1 and 2) levels. Furthermore, TLR4 in association with translocation to cytoplasm leads to macrophage motility or migration through increased plasticity of skeleton and/or membrane structure. These results suggest that oridonin-induced phagocytosis of apoptotic bodies by macrophages is TLR4 signal pathway-mediated, via activation of the autophagy-lysosome pathway as well as increase of cell migration.