PDF(Pubmed)
Abstract：
Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in CX3CR1 GFP/+ mice of both sexes led to robust elimination of resident macrophages (∼94%) without significant adverse effects on peripheral leukocytes, cochlear function, and structure. At 1 day (d) post noise exposure of 93 or 90 dB SPL for 2 hours, the degree of hearing loss and synapse loss were comparable in the presence and absence of macrophages. At 30 d after exposure, damaged synapses appeared repaired in the presence of macrophages. However, in the absence of macrophages, such synaptic repair was significantly reduced. Remarkably, on cessation of PLX5622 treatment, macrophages repopulated the cochlea, leading to enhanced synaptic repair. Elevated auditory brainstem response thresholds and reduced auditory brainstem response Peak 1 amplitudes showed limited recovery in the absence of macrophages but recovered similarly with resident and repopulated macrophages. Cochlear neuron loss was augmented in the absence of macrophages but showed preservation with resident and repopulated macrophages after noise exposure. While the central auditory effects of PLX5622 treatment and microglia depletion remain to be investigated, these data demonstrate that macrophages do not affect synaptic degeneration but are necessary and sufficient to restore cochlear synapses and function after noise-induced synaptopathy.SIGNIFICANCE STATEMENT The synaptic connections between cochlear inner hair cells and spiral ganglion neurons can be lost because of noise over exposure or biological aging. This loss may represent the most common causes of sensorineural hearing loss also known as hidden hearing loss. Synaptic loss results in degradation of auditory information, leading to difficulty in listening in noisy environments and other auditory perceptual disorders. We demonstrate that resident macrophages of the cochlea are necessary and sufficient to restore synapses and function following synaptopathic noise exposure. Our work reveals a novel role for innate-immune cells, such as macrophages in synaptic repair, that could be harnessed to regenerate lost ribbon synapses in noise- or age-linked cochlear synaptopathy, hidden hearing loss, and associated perceptual anomalies.
摘要：
在噪声诱发的突触作用后，居民耳蜗巨噬细胞迅速迁移到内毛细胞突触区，并直接接触受损的突触连接。最终,这种受损的突触被自发修复，但是巨噬细胞在突触变性和修复中的确切作用仍然未知。为了解决这个问题，使用集落刺激因子1受体（CSF1R）抑制剂消除耳蜗巨噬细胞，PLX5622。用PLX5622在CX3CR1GFP/+小鼠的两种性别的持续治疗导致了常驻巨噬细胞的强力消除（~94%），而对外周白细胞没有显著的不利影响，耳蜗功能，和结构。在93或90dBSPL的噪声暴露2小时后1天，在存在和不存在巨噬细胞的情况下，听力损失和突触损失的程度相当。暴露后30天，受损的突触在巨噬细胞的存在下出现修复。然而,在没有巨噬细胞的情况下，这种突触修复显著减少。值得注意的是,停止PLX5622治疗后，巨噬细胞重新填充耳蜗，导致突触修复增强。听觉脑干反应（ABR）阈值升高和ABR峰值1振幅降低显示在没有巨噬细胞的情况下恢复有限，但与居民和重新繁殖的巨噬细胞恢复类似。在没有巨噬细胞的情况下，耳蜗神经元丢失增加，但在噪声暴露后，显示出与常驻和重新填充的巨噬细胞的保存。虽然PLX5622治疗和小胶质细胞耗竭的中枢听觉效应仍有待研究，这些数据表明,巨噬细胞不影响突触变性,但对于噪声诱发的突触病变后恢复耳蜗突触和功能是必要且充分的.显著性陈述耳蜗内毛细胞和螺旋神经节神经元之间的突触连接可能由于暴露或生物老化而丧失。这种损失可能是感音神经性听力损失的最常见原因，也称为隐性听力损失。突触损失导致听觉信息的退化,导致在嘈杂的环境中难以听和其他听觉感知障碍。我们证明，耳蜗的常驻巨噬细胞对于在突触病变噪声暴露后恢复突触和功能是必要且足够的。我们的工作揭示了先天免疫细胞，如巨噬细胞在突触修复中的新作用，可以用来再生噪声或年龄相关的耳蜗突触中丢失的带状突触。隐藏的听力损失和相关的知觉异常。
