Department of Otolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Otolaryngology, Guangdong Women and Children Hospital, Guangzhou, China.
Exp Gerontol. 2024 May;189:112401. doi: 10.1016/j.exger.2024.112401. Epub 2024 Mar 16.
Age-related hearing loss (ARHL) is the most common sensory disorder associated with human aging. Chronic inflammation is supposed to be an important contributor to ARHL. Yet, the underlying mechanisms of developing cochlear inflammation are still not well understood. In this study, we found that the inflammation, endoplasmic reticulum (ER) stress and necroptosis signalings are activated in the cochlea of aged C57BL/6 mice. ER stress activator tunicamycin (TM) induced necroptosis in cochlear HEI-OC1 cells and cochlear explants, while necroptosis inhibitors protected cochlear cells from ER stress-induced cell death. The antioxidants inhibited necroptosis and protected HEI-OC1 cells from TM insults. Necroptotic HEI-OC1 cells promoted the activation of the co-cultured macrophages via Myd88 signaling. Moreover, necroptosis inhibitor protected from TM-induced hearing loss, and inhibited inflammation in C57BL/6 mice. These findings suggest that ER stress-induced necroptosis promotes cochlear inflammation and hearing loss. Targeting necroptosis serves as a potential approach for the treatment of cochlear inflammation and ARHL.
年龄相关性听力损失（ARHL）是与人类衰老相关的最常见感觉障碍。慢性炎症被认为是 ARHL 的一个重要贡献者。然而，耳蜗炎症发展的潜在机制仍未得到很好的理解。在这项研究中，我们发现衰老 C57BL/6 小鼠耳蜗中炎症、内质网（ER）应激和坏死信号被激活。ER 应激激活剂衣霉素（TM）诱导耳蜗 HEI-OC1 细胞和耳蜗外植体发生坏死，而坏死抑制剂可保护耳蜗细胞免受 ER 应激诱导的细胞死亡。抗氧化剂抑制坏死并保护 HEI-OC1 细胞免受 TM 损伤。坏死的 HEI-OC1 细胞通过 Myd88 信号促进共培养的巨噬细胞的激活。此外，坏死抑制剂可防止 TM 诱导的听力损失，并抑制 C57BL/6 小鼠的炎症。这些发现表明，ER 应激诱导的坏死促进耳蜗炎症和听力损失。靶向坏死可能是治疗耳蜗炎症和 ARHL 的一种潜在方法。
