Role of Spiral Ligament Fibrocytes in Immune-Mediated Inner Ear Damage

项目摘要/摘要 免疫介导性感音神经性耳聋(IMSNHL)具有重要的临床意义 渐进的双边参与和潜在的可逆性。目前，针对这些疾病的治疗目标 由于其分子发病机制尚不清楚，目前尚不能获得IMSNHL。我们的长期目标是 阐明免疫介导的内耳损伤导致SNHL的分子机制。 IMSNHL的发病机制在很大程度上尚不清楚，但无论启动因素如何，最终的病程 IMSNHL的发生通常与免疫介导的耳蜗细胞损伤(感觉细胞和非感觉细胞)有关 感官)。免疫介导的组织损伤通常涉及通过表面分子的直接细胞-细胞信号 例如抗体依赖细胞毒性；以及通过诸如肿瘤坏死因子-a的细胞因子的间接信号 (肿瘤坏死因子-a)。 以前，我们已经证明螺旋韧带纤维细胞(SLF)在反应中释放介质。 炎症信号和SLF衍生的分子直接吸引炎症细胞。因此，我们 假设SLF是免疫介导的内耳损伤的关键因素 介体和释放具有化学吸引力和细胞毒性的分子。我们还发现，肿瘤坏死因子-α的分泌是 顺铂所致耳毒性所需及下调肿瘤坏死因子-α可减轻顺铂所致耳毒性 听觉受损。这些结果导致我们将重点放在肿瘤坏死因子-α介导的细胞毒性作为免疫-免疫的一种机制。 造成内耳损伤。 然而，听觉感觉细胞似乎只有在极高的浓度下才会受到损害。 动物实验中对肿瘤坏死因子-α的影响，提示对肿瘤坏死因子-α介导的内耳有致敏作用 细胞毒性。因此，我们的目标是确定SLF诱导肿瘤坏死因子-α的分子机制 对IL-1，一种模型炎症介质的反应；和(2)使听觉感觉细胞敏化以诱导 干扰素-g介导的肿瘤坏死因子-α细胞毒作用。此外，我们计划确定治疗潜力 靶向干扰素-g致敏的肿瘤坏死因子-a介导的细胞毒作用的关键分子，这将为我们提供 为制定管理IMSNHL的新战略提供了科学依据。

Project Summary/Abstract Immune-mediated sensorineural hearing loss (IMSNHL) is of clinical importance because of progressive bilateral involvement and potential reversibility. Currently, the therapeutic targets specific to IMSNHL are not available because its molecular pathogenesis is poorly understood. Our long-term goal is to elucidate the molecular mechanism of immune-mediated inner ear damage, resulting in SNHL. Etiopathogenesis of IMSNHL is largely unknown, but regardless of the initiating factors, the final course of IMSNHL is commonly associated with immune-mediated damage of the cochlear cells (sensory and non- sensory). Immune-mediated tissue damage generally involves direct cell-cell signaling via surface molecules such as antibody-dependent cytotoxicity; and indirect signaling via cytokines such as tumor necrosis factor-a (TNF-a). Previously, we have demonstrated that spiral ligament fibrocytes (SLFs) release mediators in response to inflammatory signals and SLF-derived molecules directly attract the inflammatory cells. Therefore, we hypothesize that SLFs are key players in immune-mediated inner ear damage by responding to inflammatory mediators and releasing chemoattractive and cytotoxic molecules. We also found that secretion of TNF-a is required for cisplatin-induced ototoxicity and that down-regulation of TNF-a attenuates cisplatin-induced auditory damage. These results led us to focus on TNF-a-mediated cytotoxicity as a mechanism of immune- mediated inner ear damage. However, the auditory sensory cells appeared to be damaged only by the extremely high concentration of TNF-a in animal experiments, indicating the requirement of sensitization for TNF-a-mediated inner ear cytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-a induction in response to IL-1, a model inflammatory mediator; and (2) sensitization of the auditory sensory cells to induce TNF-a-mediated cytotoxicity via interferon-g (IFN-g). In addition, we plan to determine the therapeutic potential of targeting the key molecules involved in IFN-g-sensitized TNF-a-mediated cytotoxicity, which will provide us with a scientific basis for the development of a novel strategy to manage IMSNHL.