Vethanayagam R R, Yang W, Dong Y, Hu B H
Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA.
Cell Death Dis. 2016 Jun 2;7(6):e2245. doi: 10.1038/cddis.2016.156.
Acoustic overstimulation traumatizes the cochlea, resulting in auditory dysfunction. As a consequence of acoustic injury, the immune system in the cochlea is activated, leading to the production of inflammatory mediators and the infiltration of immune cells. However, the molecular mechanisms responsible for initiating these immune responses remain unclear. Here, we investigate the functional role of Toll-like receptor 4 (Tlr4), a cellular receptor that activates the innate immune system, in the regulation of cochlear responses to acoustic overstimulation. Using a Tlr4 knockout mouse model, we examined how Tlr4 deficiency affects sensory cell pathogenesis, auditory dysfunction and cochlear immune activity. We demonstrate that Tlr4 knockout does not affect sensory cell viability under physiological conditions, but reduces the level of sensory cell damage and cochlear dysfunction after acoustic injury. Together, these findings suggest that Tlr4 promotes sensory cell degeneration and cochlear dysfunction after acoustic injury. Acoustic injury provokes a site-dependent inflammatory response in both the organ of Corti and the tissues of the lateral wall and basilar membrane. Tlr4 deficiency affects these inflammatory responses in a site-dependent manner. In the organ of Corti, loss of Tlr4 function suppresses the production of interleukin 6 (Il6), a pro-inflammatory molecule, after acoustic injury. By contrast, the production of inflammatory mediators, including Il6, persists in the lateral wall and basilar membrane. In addition to immune molecules, Tlr4 knockout inhibits the expression of major histocompatibility complex class II, an antigen-presenting molecule, in macrophages, suggesting that Tlr4 participates in the antigen-presenting function of macrophages after acoustic trauma. Together, these results suggest that Tlr4 regulates multiple aspects of the immune response in the cochlea and contributes to cochlear pathogenesis after acoustic injury.
声学过度刺激会损伤耳蜗，导致听觉功能障碍。作为声学损伤的结果，耳蜗中的免疫系统被激活，导致炎症介质的产生和免疫细胞的浸润。然而，引发这些免疫反应的分子机制仍不清楚。在这里，我们研究了Toll样受体4（Tlr4），一种激活先天免疫系统的细胞受体，在调节耳蜗对声学过度刺激的反应中的功能作用。使用Tlr4基因敲除小鼠模型，我们研究了Tlr4缺陷如何影响感觉细胞发病机制、听觉功能障碍和耳蜗免疫活性。我们证明，在生理条件下，Tlr4基因敲除不影响感觉细胞的活力，但在声学损伤后可降低感觉细胞损伤水平和耳蜗功能障碍。总之，这些发现表明，Tlr4在声学损伤后促进感觉细胞变性和耳蜗功能障碍。声学损伤在柯蒂氏器以及外侧壁和基底膜组织中引发了位点依赖性炎症反应。Tlr4缺陷以位点依赖性方式影响这些炎症反应。在柯蒂氏器中，Tlr4功能丧失会抑制声学损伤后促炎分子白细胞介素6（Il6）的产生。相比之下，包括Il6在内的炎症介质在外侧壁和基底膜中持续存在。除了免疫分子外，Tlr4基因敲除还抑制巨噬细胞中主要组织相容性复合体II类分子（一种抗原呈递分子）的表达，这表明Tlr4在声学创伤后参与巨噬细胞的抗原呈递功能。总之，这些结果表明，Tlr4调节耳蜗免疫反应的多个方面，并在声学损伤后促进耳蜗发病机制。
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