Zhao Zihe, Li Ao, Zhu Yan, Cen Shaoqin, Liu Qing, Zhang Yuan, Fan Hanqi, Hou Zhenxing, Ma Dengbin, Liu Dingding, Duan Maoli, Qian Xiaoyun, Chai Renjie, Wan Guoqiang, Gao Xia
Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Research Institute of Otolaryngology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2423240122. doi: 10.1073/pnas.2423240122. Epub 2025 Aug 12.
Hearing loss (HL) in patients with systemic lupus erythematosus (SLE) has been widely reported, though the underlying mechanisms remain unclear. In this study, we demonstrate significant HL in an imiquimod-induced mouse model of SLE, accompanied by blood-labyrinth barrier (BLB) damage in the stria vascularis (SV). We found that cytotoxic CD8 T lymphocytes and natural killer cells mediate BLB disruption, with granzyme b (Gzmb) acting as the primary factor inducing cell death of the cochlear capillary endothelial cells. Remarkably, inhibiting Gzmb by Serpinb9 significantly alleviates the elevations of hearing thresholds in imiquimod-induced SLE model mice, suggesting a therapeutic target for autoimmune-related HL. Our findings provide insights into the pathogenesis of SLE-related HL and propose Gzmb inhibition as a potential therapeutic strategy.
系统性红斑狼疮（SLE）患者的听力损失（HL）已被广泛报道，但其潜在机制仍不清楚。在本研究中，我们在咪喹莫特诱导的SLE小鼠模型中证实了显著的HL，并伴有血管纹（SV）中的血迷路屏障（BLB）损伤。我们发现细胞毒性CD8 T淋巴细胞和自然杀伤细胞介导BLB破坏，颗粒酶b（Gzmb）是诱导耳蜗毛细血管内皮细胞死亡的主要因素。值得注意的是，通过Serpinb9抑制Gzmb可显著减轻咪喹莫特诱导的SLE模型小鼠听力阈值的升高，提示其为自身免疫相关HL的治疗靶点。我们的研究结果为SLE相关HL的发病机制提供了见解，并提出抑制Gzmb作为一种潜在的治疗策略。
