Blood–labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus
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<sup>+</sup> 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.
Authors
- Xia Gao (ORCID: https://orcid.org/0000-0002-4539-5929)
- Shaoqin Cen
- Xiaoyun Qian (ORCID: https://orcid.org/0000-0001-7779-437X)
- Dingding Liu (ORCID: https://orcid.org/0000-0002-8724-036X)
- Renjie Chai (ORCID: https://orcid.org/0000-0002-3885-543X)
- Yan Zhu (ORCID: https://orcid.org/0000-0002-5993-4110)
- Qing Liu (ORCID: https://orcid.org/0000-0002-0257-0694)
- Guoqiang Wan (ORCID: https://orcid.org/0000-0003-3841-9301)
- Maoli Duan (ORCID: https://orcid.org/0000-0002-8437-1583)
- Dengbin Ma
- Zihe Zhao (ORCID: https://orcid.org/0000-0001-9834-7720)
- Ao Li (ORCID: https://orcid.org/0000-0001-7861-6313)
- Yuan Zhang (ORCID: https://orcid.org/0000-0003-3770-0046)
- Haining Fan (ORCID: https://orcid.org/0000-0001-9231-7969)
- Zhenyuan Hou (ORCID: https://orcid.org/0000-0001-9435-099X)
Institutions
- Karolinska University Hospital (SE)
- Fudan University (CN)
- Karolinska Institutet (SE)
- Research Institute of Radiology (BY)
- Zhongda Hospital Southeast University (CN)
- Nanjing Drum Tower Hospital (CN)
- Model Animal Research Center (CN)
- State Key Laboratory of Digital Medical Engineering (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1073/pnas.2423240122
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province