Journal
EMBO REPORTS
Volume 22, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embr.202051280
Keywords
chemotherapy; cisplatin; hearing loss; ototoxicity; TLR4
Categories
Funding
- Canadian Institutes of Health Research [MY2-155361, FN 2489]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2019-04825]
- Li Ka Shing Institute of Virology (LKSIoV) (LKSIOVSF)
- Stollery Children's Hospital Foundation through the Women and Children's Health Research Institute (WCHRI) [WCHRIRRG 1958]
- Kids with Cancer Society
- WCHRI [2631, 2749]
- Alberta Cancer Foundation [27176]
- LKSIoV
- Canada Research Chairs Program [231622]
- Faculty of Medicine Dentistry
- Canada Foundation for Innovation (CFI)
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The study found that TLR4 can be activated by platinum and cisplatin, playing a key role in cisplatin-induced hair cell damage. Thus, TLR4 may be a promising therapeutic target to mitigate cisplatin-induced ototoxicity (CIO).
Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and can also be activated by some Group 9/10 transition metals, which is believed to mediate immune hypersensitivity reactions. In this work, we test whether TLR4 can be activated by the Group 10 metal platinum and the platinum-based chemotherapeutic cisplatin. Cisplatin is invaluable in childhood cancer treatment but its use is limited due to a permanent hearing loss (cisplatin-induced ototoxicity, CIO) adverse effect. We demonstrate that platinum and cisplatin activate pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. We further show that TLR4 is required for cisplatin-induced inflammatory, oxidative, and cell death responses in hair cells in vitro and for hair cell damage in vivo. Finally, we identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Thus, our findings indicate that TLR4 is a promising therapeutic target to mitigate CIO.
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