2. Academic Validation
  3. Single-Cell Sequencing Reveals Circadian Sensitivity of Noise-Induced Hearing Loss Mediated by Macrophage-Driven NLRP3 Inflammasome Activation

Single-Cell Sequencing Reveals Circadian Sensitivity of Noise-Induced Hearing Loss Mediated by Macrophage-Driven NLRP3 Inflammasome Activation

  • Neurosci Bull. 2025 Jul 20. doi: 10.1007/s12264-025-01440-1.
Qingping Ma # 1 2 3,  Qixuan Wang # 4,  Zixuan Zhu # 5,  Qian Zhou 1 2 3,  Zhongying Wang 1 2 3,  Minfei Qian 6,  Teng Li 5,  Xixi Gu 5,  Zechuan Chen 5,  Xueling Wang 7 8 9,  Xiaoming Zhang 10,  Zhiwu Huang 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 2 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China.
  • 3 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200125, China.
  • 4 Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital of Fudan University, ENT Institute, Eye & ENT Hospital of Fudan University, NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China.
  • 5 National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6 Department of Otolaryngology-Head and Neck Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 7 Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. xuelingwang2013@163.com.
  • 8 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200125, China. xuelingwang2013@163.com.
  • 9 Biobank, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China. xuelingwang2013@163.com.
  • 10 National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China. xmzhang@ips.ac.cn.
  • 11 Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. huangzw86@126.com.
  • 12 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China. huangzw86@126.com.
  • 13 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200125, China. huangzw86@126.com.
  • 14 College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. huangzw86@126.com.
  • # Contributed equally.
PMID: 40684422 DOI: 10.1007/s12264-025-01440-1
Abstract

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.

Keywords

Circadian rhythm; Macrophage; NLRP3 inflammasome; Noise-induced hearing loss.

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