Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity.
Ghazal BabolmoradAsna LatifIvan K DomingoNiall M PollockCole DelyeaAja M RiegerW Ted AllisonAmit P BhavsarPublished in: EMBO reports (2021)
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.
Keyphrases
- toll like receptor
- inflammatory response
- nuclear factor
- immune response
- small molecule
- cell death
- oxidative stress
- lps induced
- cell cycle arrest
- induced apoptosis
- stem cells
- gold nanoparticles
- hearing loss
- emergency department
- signaling pathway
- risk assessment
- climate change
- anti inflammatory
- carbon nanotubes
- human health