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

• Published in: EMBO reports 2021-05, Vol.22 (5), p.e51280-n/a
• Main Authors: Babolmorad, Ghazal, Latif, Asna, Domingo, Ivan K, Pollock, Niall M, Delyea, Cole, Rieger, Aja M, Allison, W Ted, Bhavsar, Amit P
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - adverse effects; Apoptosis; Biocompatibility; Cancer; Cancer therapies; Cell death; Chemotherapy; Children; Cisplatin; Cisplatin - toxicity; Damage; EMBO08; EMBO19; EMBO37; Hair; Hair cells; Hearing loss; Hearing protection; Heavy metals; Humans; Hypersensitivity; In vivo methods and tests; Inflammation; Inhibitors; Lipopolysaccharides; Mortality; Neoplasms - drug therapy; Nickel; Ototoxicity; Platinum; Platinum - therapeutic use; Receptors; TLR4; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Toxicity; Transition metals; Zebrafish
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202051280

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. SYNOPSIS Cisplatin is invaluable in cancer treatment, but its use is limited due to cisplatin-induced ototoxicity. TLR4 is activated by cisplatin, contributing to cisplatin-induced hair cell death, but genetic and small molecule inhibition of TLR4 curtails ototoxicity. Platinum and the platinum-based chemotherapeutic cisplatin activate Toll-like receptor 4 (TLR4). TLR4 signaling is required for cisplatin-induced responses in hair cells and for hair cell damage. Genetic inhibition of TLR4 protects against cisplatin-induced toxicity in vitro and reduces hair cell death in zebrafish. A TLR4 inhibitor prevents ototoxic cisplatin responses in vitro . Graphical Abstract Cisplatin is invaluable in cancer treatment, but its use is limited due to cisplatin-induced ototoxicity. TLR4 is activated by cisplatin, contributing to cisplatin-induced hair cell death, but genetic and small molecule inhibition of TLR4 curtails ototoxicity.