{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Babolmorad G"],"funding":["Natural Sciences and Engineering Research Council of Canada","Alberta Cancer Foundation","Kids With Cancer Society","Canadian Institutes of Health Research","Canada Research Chairs","CIHR"],"pagination":["e51280"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8097357"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["22(5)"],"pubmed_abstract":["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."],"journal":["EMBO reports"],"pubmed_title":["Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity."],"pmcid":["PMC8097357"],"funding_grant_id":["27176","MY2-155361","2631","RGPIN‐2019‐04825","231622","MY2‐155361"],"pubmed_authors":["Bhavsar AP","Domingo IK","Delyea C","Rieger AM","Pollock NM","Babolmorad G","Latif A","Allison WT"],"additional_accession":[]},"is_claimable":false,"name":"Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 May","modification":"2025-04-19T02:33:58.914Z","creation":"2025-04-07T12:59:50.38Z"},"accession":"S-EPMC8097357","cross_references":{"pubmed":["33733573"],"doi":["10.15252/embr.202051280"]}}