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

描述（由申请人提供）：免疫介导的感音神经性听力损失（IMSNHL）由于进行性双侧受累和潜在的可逆性而具有临床重要性。目前，由于对IMSNHL的分子发病机制了解甚少，无法获得特异性的治疗靶点。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是未知的，但无论起始因素如何，IMSNHL的最终病程通常与耳蜗细胞（感觉和非感觉）的免疫介导损伤有关。免疫介导的组织损伤通常涉及通过表面分子（如抗体依赖性细胞毒性）直接的细胞-细胞信号传导；以及通过肿瘤坏死因子（TNF-）等细胞因子间接传递信号。先前，我们已经证明螺旋韧带纤维细胞（slf）释放介质响应炎症信号，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参与者，通过对炎症介质作出反应并释放化学吸引和细胞毒性分子。我们还发现，分泌TNF-(是顺铂诱导的耳毒性所必需的，TNF-(的下调可减轻顺铂诱导的听觉损伤。这些结果使我们关注TNF-介导的细胞毒性作为免疫介导的内耳损伤的机制。然而，在动物实验中，听觉感觉细胞似乎只被极高浓度的TNF-(（）损伤，这表明需要对TNF-（）介导的内耳细胞毒性致敏。因此，我们的目标是确定参与其中的分子机制：(1)SLF对IL-1（一种模型炎症介质）的TNF-诱导反应；(2)听觉细胞通过干扰素-(IFN-（）致敏，诱导TNF-（）介导的细胞毒性。此外，我们计划确定靶向IFN-致敏TNF-介导的细胞毒性的关键分子的治疗潜力，这将为我们开发管理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.