Department of Otorhinolaryngology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hear Res. 2021 Dec;412:108378. doi: 10.1016/j.heares.2021.108378. Epub 2021 Oct 23.
Acoustic trauma induces an inflammatory response in the cochlea, resulting in debilitating hearing function. Clinically, amelioration of inflammation substantially prevents noise-induced hearing loss. The Limulus factor C, Cochlin, and Lgl1 (LCCL) peptide plays an important role in innate immunity during bacteria-induced inflammation in the cochlea. We aimed to investigate the LCCL-induced innate immune response to noise exposure and its impact on hearing function.
We used Coch (encodes cochlin harboring LCCL peptide) knock-out and p.G88E knock-in mice to compare the immune responses before and after noise exposure. We explored their hearing function and hair cell degeneration. Moreover, we investigated distinct characteristics of immune responses upon noise exposure using flow cytometry and RNA sequencing.
One day after noise exposure, the LCCL peptide cleaved from cochlin increased over time in the perilymph space. Both Coch and Coch mutant mice revealed more preserved hearing following acoustic trauma compared to wild-type mice. The outer hair cells were more preserved in Coch than in wild-type mice upon noise exposure. The RNA sequencing data demonstrated significantly upregulated cell migration gene ontology in wild-type mice than in Coch mice following noise exposure, indicating that the infiltration of immune cells was dependent on cochlin. Notably, infiltrated monocytes from blood (C11b/Ly6G/Ly6C) were remarkably higher in wild-type mice than in Coch mice at 1 day after noise exposure.
Noise-induced hearing loss was attributed to over-stimulated cochlin, and led to the cleavage and secretion of LCCL peptide in the cochlea. The LCCL peptide recruited more monocytes from the blood vessels upon noise stimulation, thus highlighting a novel therapeutic target for noise-induced hearing loss.
声创伤会在耳蜗中引起炎症反应，导致听力功能受损。临床上，减轻炎症可显著预防噪声性听力损失。鲎因子 C、Cochlin 和 Lgl1（LCCL）肽在细菌诱导的耳蜗炎症中先天免疫中起着重要作用。我们旨在研究 LCCL 诱导的对噪声暴露的先天免疫反应及其对听力功能的影响。
我们使用 Coch（编码含有 LCCL 肽的 Cochlin）敲除和 p.G88E 敲入小鼠来比较噪声暴露前后的免疫反应。我们探索了它们的听力功能和毛细胞变性。此外，我们使用流式细胞术和 RNA 测序研究了噪声暴露后不同的免疫反应特征。
噪声暴露后 1 天，来自 Cochlin 的 LCCL 肽在耳淋巴液空间中随时间推移而增加。与野生型小鼠相比，Coch 和 Coch 突变型小鼠在声学创伤后具有更明显的听力保留。与野生型小鼠相比，噪声暴露后 Coch 中的外毛细胞更能保留。RNA 测序数据表明，与 Coch 小鼠相比，噪声暴露后野生型小鼠中的细胞迁移基因本体论显著上调，表明免疫细胞的浸润依赖于 Cochlin。值得注意的是，噪声暴露后 1 天，来自血液的浸润单核细胞（C11b/Ly6G/Ly6C）在野生型小鼠中明显高于 Coch 小鼠。
噪声性听力损失归因于过度刺激的 Cochlin，导致 Cochlea 中 LCCL 肽的切割和分泌。LCCL 肽在噪声刺激下从血管招募更多的单核细胞，因此突出了噪声性听力损失的一个新的治疗靶点。
