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

描述(申请人提供)：免疫介导性感音神经性听力损失(IMSNHL)具有进行性双侧受累和潜在的可逆性，具有临床重要性。目前，针对IMSNHL的特异性治疗靶点尚不清楚，因为其分子发病机制尚不清楚。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的发病机制很大程度上尚不清楚，但无论启动因素如何，IMSNHL的最终病程通常与免疫介导的耳蜗细胞(感觉和非感觉)损伤有关。免疫介导的组织损伤通常包括通过抗体依赖的细胞毒性等表面分子的直接细胞-细胞信号转导，以及通过肿瘤坏死因子(TNF-())等细胞因子的间接信号转导。以前，我们已经证明螺旋韧带纤维细胞(SLF)在响应炎症信号时释放介质，并且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中的关键角色，通过对炎症介质的反应和释放具有趋化性和细胞毒性的分子。我们还发现，肿瘤坏死因子-1的分泌是顺铂所致耳毒性所必需的，而肿瘤坏死因子-1的下调可减轻顺铂所致的听力损伤。这些结果使我们将重点放在了肿瘤坏死因子介导的细胞毒性作为免疫介导的内耳损伤的机制上。然而，在动物实验中，听觉感觉细胞似乎只受到极高浓度的肿瘤坏死因子-1的损伤，这表明需要对肿瘤坏死因子-1介导的内耳细胞毒性进行增敏。因此，我们的目标是确定SLF的分子机制：(1)SLF对模型炎症介质IL-1的诱导；(2)通过干扰素-(干扰素-())敏化听觉感觉细胞，诱导肿瘤坏死因子-介导的细胞毒作用。此外，我们计划确定针对干扰素致敏的肿瘤坏死因子介导的细胞毒作用的关键分子的治疗潜力，这将为开发治疗IMSNHL的新策略提供科学依据。

DESCRIPTION (provided by applicant): 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-( (TNF-(). 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-( is required for cisplatin-induced ototoxicity and that down-regulation of TNF-( attenuates cisplatin-induced auditory damage. These results led us to focus on TNF-(-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-( in animal experiments, indicating the requirement of sensitization for TNF-(-mediated inner ear cytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-( induction in response to IL-1, a model inflammatory mediator; and (2) sensitization of the auditory sensory cells to induce TNF-(-mediated cytotoxicity via interferon-( (IFN-(). In addition, we plan to determine the therapeutic potential of targeting the key molecules involved in IFN-(-sensitized TNF-(-mediated cytotoxicity, which will provide us with a scientific basis for the development of a novel strategy to manage IMSNHL.