Inhibition of the activation and recruitment of microglia-like cells protects against neomycin-induced ototoxicity.

Abstract

One of the most unfortunate side effects of aminoglycoside (AG) antibiotics such as neomycin is that they target sensory hair cells (HCs) and can cause permanent hearing impairment. We have observed HC loss and microglia-like cell (MLC) activation in the inner ear (cochlea) following neomycin administration. We focused on CX3CL1, a membrane-bound glycoprotein expressed on neurons and endothelial cells, as a way to understand how the MLCs are activated and the role these cells play in HC loss. CX3CL1 is the exclusive ligand for CX3CR1, which is a chemokine receptor expressed on the surface of macrophages and MLCs. In vitro experiments showed that the expression levels of CX3CL1 and CX3CR1 increased in the cochlea upon neomycin treatment, and CX3CL1 was expressed on HCs, while CX3CR1 was expressed on MLCs. When cultured with 1 μg/mL exogenous CX3CL1, MLCs were activated by CX3CL1, and the cytokine level was increased in the cochleae leading to apoptosis in the HCs. In CX3CR1 knockout mice, a significantly greater number of cochlear HCs survived than in wild-type mice when the cochlear explants were cultured with neomycin in vitro. Furthermore, inhibiting the activation of MLCs with minocycline reduced the neomycin-induced HC loss and improved the hearing function in neomycin-treated mice in vivo. Our results demonstrate that CX3CL1-induced MLC activation plays an important role in the induction of HC death and provide evidence for CX3CL1 and CX3CR1 as promising new therapeutic targets for the prevention of hearing loss.

• Authors: Shan Sun, Huiqian Yu, Hui Yu, Mei Honglin, Wenli Ni, Yanping Zhang, Luo Guo, Yingzi He, Zhen Xue, Yusu Ni, Jin Li, Yi Feng, Yan Chen, Ruijin Shao, Renjie Chai, Huawei Li
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 51 Issue 1 Pg. 252-67 (Feb 2015) ISSN: 1559-1182 [Electronic] United States
• PMID: 24781382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• CX3C Chemokine Receptor 1
• Chemokine CX3CL1
• Cx3cr1 protein, mouse
• Myosin Light Chains
• Receptors, Chemokine
• Minocycline
• Neomycin

Topics

• Animals
• Antibodies, Neutralizing (pharmacology)
• CX3C Chemokine Receptor 1
• Cells, Cultured
• Chemokine CX3CL1 (metabolism, pharmacology)
• Cochlea (drug effects, pathology)
• Ear Diseases (chemically induced, metabolism, pathology)
• Hair Cells, Auditory (drug effects, metabolism, pathology)
• Hearing Loss (chemically induced, complications, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (drug effects, pathology)
• Minocycline (pharmacology)
• Myosin Light Chains (metabolism)
• Neomycin (administration & dosage, adverse effects)
• Protein Biosynthesis (drug effects)
• Receptors, Chemokine (deficiency, metabolism)
• Up-Regulation (drug effects)