Interplay between RAGE and TLR4 Regulates HMGB1-Induced Inflammation by Promoting Cell Surface Expression of RAGE and TLR4
Interplay between RAGE and TLR4 Regulates HMGB1-Induced Inflammation by Promoting Cell Surface Expression of RAGE and TLR4
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RAGE 和 TLR4 之间的相互作用通过促进 RAGE 和 TLR4 的细胞表面表达来调节 HMGB1 诱导的炎症
DOI：
10.4049/jimmunol.1900860
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Jing Tang
中科院分区：
文献类型：
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作者：
Hanhui Zhong;Xiaolian Li;Shuangnan Zhou;Ping Jiang;Xiaolei Liu;Mingwen Ouyang;Ying Nie;Xinying Chen;Liangqing Zhang;Youtan Liu;Tao Tao;Jing Tang
要点 细胞表面受体 RAGE 和 TLR4 调节 HMGB1 诱导的炎症。 RAGE 促进 TLR4 运输至细胞表面，但不影响其翻译。 TLR4 调节 RAGE 的翻译，使其易位至细胞表面。晚期糖基化终末产物受体 (RAGE) 和 TLR4 在针对高迁移率族蛋白 1 (HMGB1)（一种晚期促炎细胞因子和损伤相关分子模式）的炎症反应中发挥着重要作用。作为细胞表面受体，RAGE 和 TLR4 不断在细胞质和质膜之间运输。然而，TLR4 是否与 HMGB1 诱导的炎症中 RAGE 的细胞内转运有关仍不清楚。在这项研究中，我们证明HMGB1不仅增加细胞质和质膜中RAGE的表达，而且上调质膜中TLR4的表达。敲除 RAGE 会导致 MAPK 激活、TLR4 细胞膜表达减少以及相应的炎症细胞因子生成减少。同时，抑制 MAPK 激活也会降低 TLR4 表面表达。这些结果表明HMGB1可能与细胞表面的RAGE受体结合，导致MAPK激活，从而促进TLR4在细胞表面的易位，但不调节其转录和翻译。相反，TLR4可以增加RAGE的转录和翻译，RAGE易位到细胞表面并能够结合更多的HMGB1。细胞表面受体 TLR4 和 RAGE 与 HMGB1 结合，导致炎症细胞因子的转录和分泌。最后，我们还在小鼠假性骨折模型中观察到了这些结果，这与 HMGB1 诱导的炎症反应密切相关。所有这些结果表明，RAGE 和 TLR4 之间的相互作用对于 HMGB1 诱导的炎症反应至关重要。
Key Points The cell surface receptors RAGE and TLR4 regulate HMGB1-induced inflammation. RAGE promotes TLR4 trafficking to the cell surface but does not affect its translation. TLR4 regulates the translation of RAGE, which translocates to the cell surface. Receptor for advanced glycation end-products (RAGE) and TLR4 play an important role in the inflammatory response against High-mobility group box 1 protein (HMGB1), a late proinflammatory cytokine and a damage-associated molecular pattern. As cell surface receptors, both RAGE and TLR4 are constantly trafficking between the cytoplasm and plasma membrane. However, whether TLR4 is related to the intracellular transport of RAGE in HMGB1-induced inflammation remains unknown. In this study, we demonstrated that HMGB1 not only increased RAGE expression in both the cytoplasm and plasma membrane but also upregulated the expression of TLR4 in the plasma membrane. Knocking out of RAGE led to decreased MAPK activation, TLR4 cellular membrane expression, and corresponding inflammatory cytokine generation. Meanwhile, inhibiting MAPK activation also decreased TLR4 surface expression. These results indicated that HMGB1 may bind to cell surface RAGE receptors on the cell surface, leading to MAPK activation, thus promoting TLR4 translocation on the cell surface, but does not regulate its transcription and translation. In contrast, TLR4 can increase the transcription and translation of RAGE, which translocates to the cell surface and is able to bind to more HMGB1. The cell surface receptors TLR4 and RAGE bind to HMGB1, leading to the transcription and secretion of inflammatory cytokines. Finally, we also observed these results in the mice pseudofracture model, which is closely related to HMGB1-induced inflammatory response. All these results demonstrated that the interplay between RAGE and TLR4 are critical for HMGB1-induced inflammatory response.