感音神经性听力损失中的内耳免疫微环境：机制与治疗前景

文献信息

中文摘要

背景： 感音神经性听力损失（SNHL）影响全球超过15亿人，并且仍然是人类中最普遍的感觉缺陷。尽管经典病理模型强调氧化应激和线粒体功能障碍导致的毛细胞死亡，但过去十年中不断积累的证据已将耳蜗重新定义为免疫活跃组织，而非免疫豁免器官。方法：常驻巨噬细胞分布于螺旋韧带、血管纹、螺旋神经节和蜗轴，它们协调对声学、耳毒性、代谢和免疫应激的保护性和损伤性反应。结果：近期单细胞转录组数据已识别出疾病特异性巨噬细胞亚群，包括在年龄相关性和噪声诱导性听力损失中富集的促炎性CD74+CD14+群体。耳蜗炎症的分子驱动因素包括TNF-α、IL-1β和IL-6等细胞因子，HMGB1和HSP70等危险相关分子模式，NLRP3炎症小体激活，补体信号传导，以及血-迷路屏障的破坏。这些机制在多种SNHL病因中汇聚，从噪声诱导的突触病和老年性聋中的炎性衰老，到耳毒性、自身免疫性内耳病、突发特发性SNHL以及病毒性或病毒感染后听力损失。结论：在治疗方面，该领域正从广谱皮质类固醇转向免疫靶向策略，包括细胞因子导向的生物制剂、NLRP3抑制剂、补体靶向药物、巨噬细胞重编程、间充质干细胞来源的外泌体、鼓室内纳米颗粒递送系统，以及具有调节免疫特征的基因治疗方法。外淋巴采样现在为活体患者提供了观察耳蜗微环境的窗口，使生物标志物引导的精准医学成为可能。本综述综合了支持耳蜗免疫微环境作为SNHL发病机制中统一轴的细胞、分子和临床证据，并概述了可能在未来十年改变标准治疗的治疗前景。

英文摘要

Sensorineural hearing loss (SNHL) affects over 1.5 billion individuals worldwide and remains the most prevalent sensory deficit in humans. Although classical pathological models have emphasized hair cell death from oxidative stress and mitochondrial dysfunction, accumulating evidence over the past decade has redefined the cochlea as an immunologically active tissue rather than an immune-privileged organ. Resident macrophages populate the spiral ligament, stria vascularis, spiral ganglion, and modiolus, and they orchestrate both protective and damaging responses to acoustic, ototoxic, metabolic, and immunological stress. Recent single-cell transcriptomic data have identified disease-specific macrophage subsets, including a proinflammatory CD74+CD14+ population enriched in age-related and noise-induced hearing loss. Molecular drivers of cochlear inflammation include cytokines such as TNF-alpha, IL-1beta, and IL-6, danger-associated molecular patterns including HMGB1 and HSP70, NLRP3 inflammasome activation, complement signaling, and disruption of the blood-labyrinth barrier. These mechanisms converge across diverse SNHL etiologies, from noise-induced synaptopathy and inflammaging in presbycusis, to ototoxicity, autoimmune inner ear disease, sudden idiopathic SNHL, and viral or post-viral hearing loss. Therapeutically, the field is shifting from broad-spectrum corticosteroids toward immune-targeted strategies, including cytokine-directed biologics, NLRP3 inhibitors, complement-targeted agents, macrophage reprogramming, mesenchymal stem cell-derived exosomes, intratympanic nanoparticle delivery systems, and gene therapy approaches with regulated immune profiles. Perilymph sampling now offers a window into the cochlear microenvironment in living patients, enabling biomarker-guided precision medicine. This review synthesizes the cellular, molecular, and clinical evidence supporting the cochlear immune microenvironment as a unifying axis in SNHL pathogenesis, and outlines therapeutic perspectives that may transform the standard of care over the next decade.