Ma Qingping, Wang Qixuan, Zhu Zixuan, Zhou Qian, Wang Zhongying, Qian Minfei, Li Teng, Gu Xixi, Chen Zechuan, Wang Xueling, Zhang Xiaoming, Huang Zhiwu
Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China.
Neurosci Bull. 2025 Jul 20. doi: 10.1007/s12264-025-01440-1.
Circadian sensitivity significantly influences the severity of noise-induced hearing loss (NIHL), but the underlying mechanisms remain unclear. Here, we applied single-cell RNA sequencing to 97,043 cochlear cells, identifying macrophages as the primary immune responders to acoustic trauma, with a notable increase in their proportion in the cochlea. Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure, while in vivo macrophage depletion resulted in the recovery of hearing. Furthermore, analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure. Measurements of elevated IL-1β and IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group. These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09, which mitigated inflammasome activation, preserved synaptic integrity, and protect against hearing loss. In conclusion, our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage, offering a potential therapeutic target for mitigating NIHL.
昼夜节律敏感性显著影响噪声性听力损失（NIHL）的严重程度，但其潜在机制仍不清楚。在此，我们对97,043个耳蜗细胞进行了单细胞RNA测序，确定巨噬细胞是对声损伤的主要免疫应答者，其在耳蜗中的比例显著增加。免疫荧光证实噪声暴露后耳蜗巨噬细胞有显著的募集和激活，而体内巨噬细胞耗竭导致听力恢复。此外，对差异表达基因和信号通路的分析显示，夜间噪声暴露期间巨噬细胞中NLRP3炎性小体信号明显激活。通过多重免疫组织化学测量耳蜗巨噬细胞中IL-1β和IL-18表达升高，与夜间暴露组炎症加剧相关。选择性NLRP3抑制剂CY-09的给药进一步证实了这些发现，该抑制剂减轻了炎性小体激活，保留了突触完整性，并预防了听力损失。总之，我们的研究结果强调了巨噬细胞驱动的NLRP3炎性小体激活在介导耳蜗损伤昼夜变化中的作用，为减轻噪声性听力损失提供了一个潜在的治疗靶点。
