Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress
Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress
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慢性不可预测的轻度应激小鼠中，磷酸二酯酶 4 的抑制可抑制 HMGB1/RAGE 信号通路和 NLRP3 炎性体激活
DOI：
10.1016/j.bbi.2020.11.029
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Haitao Wang
中科院分区：
文献类型：
--
作者：
Jinfeng Xie;Bingtian Bi;Yunyun Qin;Wenli Dong;Jiahong Zhong;Mengfan Li;Yufang Cheng;Jiangping Xu;Haitao Wang
磷酸二酯酶 4 (PDE4) 的抑制在多种动物模型中产生强大的抗炎和抗抑郁样作用。然而，详细的机制尚未得到很好的研究。晚期糖基化终末产物 (RAGE) 受体和炎症小体激活与抑郁症的病因有关。在这里，我们的目的是研究 RAGE 和核苷酸结合域 (NOD) 样受体蛋白 3 (NLRP3) 炎症小体在小鼠 PDE4 抑制的抗抑郁样作用中的作用。我们发现，罗氟普拉姆（ROF，0.5 和 1.0 mg/kg，例如）对 PDE4 的抑制作用对遭受慢性不可预测的轻度应激 (CUMS) 的小鼠产生了类似抗抑郁的作用。同时，ROF 抑制 CUMS 诱导的小胶质细胞活化，恢复海马小胶质细胞的形态，小胶质细胞的总突起长度、面积、体积、分支点数量、终点数量和总壳交叉点的减少证明了这一点。 ROF 还降低了离子钙结合接头分子 1 的表达和白细胞介素 1β 的水平。 Western blot分析显示，PDE4抑制抑制了高迁移率族蛋白1（HMGB1）/RAGE信号通路，ROF治疗后小鼠海马和皮质中HMGB1、RAGE、Toll样受体4、磷酸化p38丝裂原激活蛋白激酶和核因子κ-B的水平均降低。此外，ROF还减弱了NLRP3、凋亡相关斑点样蛋白（ASC）和半胱氨酸需要的天冬氨酸蛋白酶-1（Caspase-1）的蛋白水平，它们是NLRP3介导的炎症小体信号通路中的关键蛋白。总之，这些结果表明 HMGB1/RAGE 信号通路的下调和炎症小体抑制可能有助于 PDE4 抑制剂的抗抑郁样作用。而且，ROF 有潜力作为治疗抑郁症的候选药物。
Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg,i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.
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影响因子：
9.3
作者：
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影响因子：
1.3
作者：
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影响因子：
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作者：
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影响因子：
5.3
作者：
Zhang L;Zhang J;You Z
通讯作者：
You Z
DOI：
10.1017/s1461145711000897
发表时间：
2012-07-01
影响因子：
4.8
作者：
Galeotti, Nicoletta;Ghelardini, Carla
通讯作者：
Ghelardini, Carla