Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus

doi:10.1073/pnas.2423240122

. 2025 Aug 19;122(33):e2423240122.

doi: 10.1073/pnas.2423240122. Epub 2025 Aug 12.

Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus

Zihe Zhao^#^{1

2}, Ao Li^#^{1

2

3

4}, Yan Zhu⁵, Shaoqin Cen^{1

2}, Qing Liu^{1

2

4}, Yuan Zhang^{1

2

3

4}, Hanqi Fan^{1

2}, Zhenxing Hou^{1

2}, Dengbin Ma^{1

2}, Dingding Liu^{2

3}, Maoli Duan^{6

7}, Xiaoyun Qian^{1

2

3

4}, Renjie Chai⁸, Guoqiang Wan^{1

2

4}, Xia Gao^{1

2

3

4}

Affiliations

¹ 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.
² Research Institute of Otolaryngology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
³ Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Drum Tower Clinical College of Nanjing Medical University, Nanjing 210008, China.
⁴ Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing 210032, China.
⁵ Institute Of Urology Nanjing University, Medical School of Nanjing University, Nanjing 210093, China.
⁶ Department of Otolaryngology Head and Neck Surgery and Audiology and Neurotology, Karolinska University Hospital, Stockholm 171 76, Sweden.
⁷ Department of Clinical Science Intervention and Technology, Karolinska Institute, Stockholm 171 77, Sweden.
⁸ State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China.

^# Contributed equally.

PMID: 40794837
DOI: 10.1073/pnas.2423240122

Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus

Zihe Zhao et al. Proc Natl Acad Sci U S A. 2025.

. 2025 Aug 19;122(33):e2423240122.

doi: 10.1073/pnas.2423240122. Epub 2025 Aug 12.

Authors

Affiliations

¹ 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.
² Research Institute of Otolaryngology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
³ Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Drum Tower Clinical College of Nanjing Medical University, Nanjing 210008, China.
⁴ Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing 210032, China.
⁵ Institute Of Urology Nanjing University, Medical School of Nanjing University, Nanjing 210093, China.
⁶ Department of Otolaryngology Head and Neck Surgery and Audiology and Neurotology, Karolinska University Hospital, Stockholm 171 76, Sweden.
⁷ Department of Clinical Science Intervention and Technology, Karolinska Institute, Stockholm 171 77, Sweden.
⁸ State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China.

^# Contributed equally.

PMID: 40794837
DOI: 10.1073/pnas.2423240122

Abstract

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.

Keywords: blood–labyrinth barrier; granzymes; hearing loss; immune-mediated cytotoxicity; systemic lupus erythematosus.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus

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Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus

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Conflict of interest statement

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