Oridonin ameliorates noise-induced hearing loss by blocking NLRP3-NEK7 mediated inflammasome activation
Oridonin ameliorates noise-induced hearing loss by blocking NLRP3-NEK7 mediated inflammasome activation
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Oridonin 通过阻断 NLRP3 - NEK7 介导的炎症小体激活来改善噪音引起的听力损失。
DOI：
10.1016/j.intimp.2021.107576
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发表时间：
2021-03-23
影响因子：
5.6
通讯作者：
Shi, Xi
中科院分区：
文献类型：
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作者：
Li, Menghua;Zhang, Yan;Shi, Xi
炎症与噪声性听力损失（NIHL）有关，但其机制尚不清楚。NOD样受体家族pyrin domain containing 3（NLRP 3）炎性体，其触发炎症级联反应，已经涉及响应于氧化应激的几种炎性疾病。然而，NLRP 3炎性小体是否是永久性NIHL的关键因素仍不清楚。在这项研究中，定量实时聚合酶链反应（qPCR），蛋白质印迹和酶联免疫吸附试验（ELISA）表明，活化的caspase-1，白细胞介素（IL）-1 β，IL-18和NLRP 3的表达水平显着增加，在小鼠耳蜗暴露于宽带噪声（120 dB）4小时，与对照组相比。这些结果表明，在NIHL的病理过程中，炎症小体在小鼠耳蜗中的激活以及NLRP 3，活性氧（ROS）的传感器蛋白，可能是炎症小体组装和随后的炎症在耳蜗中的关键因素。此外，最近的许多研究表明，NEK 7是NLRP 3炎性小体的重要组成部分和调节剂，直接与NLRP 3相互作用，并且这些相互作用可以被冬凌草甲素中断。在此，我们进一步确定了用冬凌草甲素处理确实可以中断NLRP 3和NEK 7之间的相互作用，以及抑制噪声暴露后小鼠耳蜗中下游炎性小体的激活。此外，我们测试了阿那白滞素，另一种炎症抑制剂，它被证明可以部分减轻NIHL小鼠模型中某些频率的听力损伤程度。这些发现表明，抑制NLRP 3炎性体及其下游信号通路可能为NIHL的临床治疗提供新的策略。
Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative realtime polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1 beta, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.