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

Ghazal Babolmorad, Asna Latif, Niall M. Pollock, Ivan K. Domingo, Cole Delyea, Aja M. Rieger, View ORCID ProfileW. Ted Allison, View ORCID ProfileAmit P. Bhavsar
doi: https://doi.org/10.1101/2020.06.19.162057
Ghazal Babolmorad
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Asna Latif
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Niall M. Pollock
bDepartment of Biological Sciences, Faculty of Science, CW 405, Biological Sciences Bldg., University of Alberta, Edmonton, Alberta T6G 2E9 Canada
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Ivan K. Domingo
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Cole Delyea
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Aja M. Rieger
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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W. Ted Allison
bDepartment of Biological Sciences, Faculty of Science, CW 405, Biological Sciences Bldg., University of Alberta, Edmonton, Alberta T6G 2E9 Canada
cDepartment of Medical Genetics, Faculty of Medicine & Dentistry, 8-39 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7 Canada
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  • ORCID record for W. Ted Allison
Amit P. Bhavsar
aDepartment of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
cDepartment of Medical Genetics, Faculty of Medicine & Dentistry, 8-39 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7 Canada
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  • ORCID record for Amit P. Bhavsar
  • For correspondence: amit.bhavsar@ualberta.ca
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Abstract

Toll-like receptor 4 (TLR4) is famous for recognizing the bacterial endotoxin lipopolysaccharide (LPS) as its canonical ligand. TLR4 is also activated by other classes of agonist including some Group 9/10 transition metals. Roles for these non-canonical ligands in pathobiology mostly remain obscure, though TLR4 interactions with metals can mediate immune hypersensitivity reactions. In this work, we tested whether TLR4 can be activated by the Group 10 transition metal, platinum. We demonstrated that in the presence of TLR4, platinum activates pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. Platinum is the active moiety in cisplatin, a very potent and invaluable chemotherapeutic used to treat solid tumors in childhood cancer patients. Unfortunately, cisplatin use is limited due to an adverse effect of permanent hearing loss (cisplatin-induced ototoxicity, CIO). Herein, we demonstrated that cisplatin also activates TLR4, prompting the hypothesis that TLR4 mediates aspects of CIO. Cisplatin activation of TLR4 was independent of the TLR4 co-receptors CD14 and MD-2, which is consistent with TLR4 signaling elicited by transition metals. We found that TLR4 is required for cisplatin-induced inflammatory, oxidative and apoptotic responses in an ear outer hair cell line and for hair cell damage in vivo. Thus, TLR4 is a promising therapeutic target to mitigate CIO. We additionally identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Further work is warranted towards inhibiting TLR4 as a route to mitigating this adverse outcome of childhood cancer treatment.

Significance Statement This work identifies platinum, and its derivative cisplatin, as new agonists for TLR4. TLR4 contributes to cisplatin-induced hair cell death in vitro and in vivo. Genetic and small molecule inhibition of TLR4 identify this receptor as a druggable therapeutic target with promise to curtail cisplatin-induced ototoxicity, a devastating side-effect of an otherwise invaluable chemotherapeutic tool.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 20, 2020.
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Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity
Ghazal Babolmorad, Asna Latif, Niall M. Pollock, Ivan K. Domingo, Cole Delyea, Aja M. Rieger, W. Ted Allison, Amit P. Bhavsar
bioRxiv 2020.06.19.162057; doi: https://doi.org/10.1101/2020.06.19.162057
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Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity
Ghazal Babolmorad, Asna Latif, Niall M. Pollock, Ivan K. Domingo, Cole Delyea, Aja M. Rieger, W. Ted Allison, Amit P. Bhavsar
bioRxiv 2020.06.19.162057; doi: https://doi.org/10.1101/2020.06.19.162057

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