Department of Otolaryngology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China; The First Affiliated Hospital, Jinan University, Guangzhou 510632, China; The Institute of Audiology and Balance Science of Xu zhou Medical University, Xuzhou 221004, China.
Department of Otorhinolaryngology Head and Neck Surgery, First Hospital of Jilin University, Changchun, Jilin 130021, China.
Int Immunopharmacol. 2021 Jun;95:107576. doi: 10.1016/j.intimp.2021.107576. Epub 2021 Mar 23.
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 real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1β, 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.
炎症参与了噪声性听力损失（NIHL），但其机制尚不清楚。NOD 样受体家族包含 pyrin 结构域的 3（NLRP3）炎性小体，它触发炎症级联反应，已被牵连到几种炎症性疾病中，以应对氧化应激。然而，NLRP3 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）、western blot 和酶联免疫吸附测定（ELISA）表明，与对照组相比，暴露于宽带噪声（120dB）4 小时的小鼠耳蜗中，活化的半胱天冬酶-1、白细胞介素（IL）-1β、IL-18 和 NLRP3 的表达水平显著增加。这些结果表明，在 NIHL 病理过程中小鼠耳蜗中炎性小体的激活以及 NLRP3（活性氧（ROS）的传感器蛋白）可能是炎性小体组装和随后耳蜗炎症的关键因素。此外，许多最近的研究表明，NEK7 通过直接与 NLRP3 相互作用，成为 NLRP3 炎性小体的重要组成部分和调节剂，这些相互作用可以被冬凌草甲素打断。在这里，我们进一步确定，冬凌草甲素处理确实可以中断 NLRP3 和 NEK7 之间的相互作用，并抑制噪声暴露后小鼠耳蜗中下游炎性小体的激活。此外，我们测试了另一种炎症抑制剂阿那白滞素，结果表明它可以部分缓解 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 NLRP3 炎性小体及其下游信号通路可能为 NIHL 的临床治疗提供新策略。
