Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity.

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. © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Citation

Ghazal Babolmorad, Asna Latif, Ivan K Domingo, Niall M Pollock, Cole Delyea, Aja M Rieger, W Ted Allison, Amit P Bhavsar. Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity. EMBO reports. 2021 May 05;22(5):e51280

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PMID: 33733573

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