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Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity

Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear...

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Autores principales: Al Aameri, Raheem F. H., Alanisi, Entkhab M. A., Oluwatosin, Adu, Al Sallami, Dheyaa, Sheth, Sandeep, Alberts, Ian, Patel, Shree, Rybak, Leonard P., Ramkumar, Vickram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102581/
https://www.ncbi.nlm.nih.gov/pubmed/37063917
http://dx.doi.org/10.3389/fimmu.2023.1125948
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author Al Aameri, Raheem F. H.
Alanisi, Entkhab M. A.
Oluwatosin, Adu
Al Sallami, Dheyaa
Sheth, Sandeep
Alberts, Ian
Patel, Shree
Rybak, Leonard P.
Ramkumar, Vickram
author_facet Al Aameri, Raheem F. H.
Alanisi, Entkhab M. A.
Oluwatosin, Adu
Al Sallami, Dheyaa
Sheth, Sandeep
Alberts, Ian
Patel, Shree
Rybak, Leonard P.
Ramkumar, Vickram
author_sort Al Aameri, Raheem F. H.
collection PubMed
description Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear cell death through DNA damage, the generation of reactive oxygen species (ROS) and the consequent activation of caspase, glutamate excitotoxicity, inflammation, apoptosis and/or necrosis. Previous studies have demonstrated a role of CXC chemokines in cisplatin ototoxicity. In this study, we investigated the role of CXCL1, a cytokine which increased in the serum and cochlea by 24 h following cisplatin administration. Adult male Wistar rats treated with cisplatin demonstrated significant hearing loss, assessed by auditory brainstem responses (ABRs), hair cell loss and loss of ribbon synapse. Immunohistochemical studies evaluated the levels of CXCL1 along with increased presence of CD68 and CD45-positive immune cells in cochlea. Increases in CXCL1 was time-dependent in the spiral ganglion neurons and organ of Corti and was associated with progressive increases in CD45, CD68 and IBA1-positive immune cells. Trans-tympanic administration of SB225002, a chemical inhibitor of CXCR2 (receptor target for CXCL1) reduced immune cell migration, protected against cisplatin-induced hearing loss and preserved hair cell integrity. We show that SB225002 reduced the expression of CXCL1, NOX3, iNOS, TNF-α, IL-6 and COX-2. Similarly, knockdown of CXCR2 by trans-tympanic administration of CXCR2 siRNA protected against hearing loss and loss of outer hair cells and reduced ribbon synapses. In addition, SB225002 reduced the expression of inflammatory mediators induced by cisplatin. These results implicate the CXCL1 chemokine as an early player in cisplatin ototoxicity, possibly by initiating the immune cascade, and indicate that CXCR2 is a relevant target for treating cisplatin ototoxicity.
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spelling pubmed-101025812023-04-15 Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity Al Aameri, Raheem F. H. Alanisi, Entkhab M. A. Oluwatosin, Adu Al Sallami, Dheyaa Sheth, Sandeep Alberts, Ian Patel, Shree Rybak, Leonard P. Ramkumar, Vickram Front Immunol Immunology Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear cell death through DNA damage, the generation of reactive oxygen species (ROS) and the consequent activation of caspase, glutamate excitotoxicity, inflammation, apoptosis and/or necrosis. Previous studies have demonstrated a role of CXC chemokines in cisplatin ototoxicity. In this study, we investigated the role of CXCL1, a cytokine which increased in the serum and cochlea by 24 h following cisplatin administration. Adult male Wistar rats treated with cisplatin demonstrated significant hearing loss, assessed by auditory brainstem responses (ABRs), hair cell loss and loss of ribbon synapse. Immunohistochemical studies evaluated the levels of CXCL1 along with increased presence of CD68 and CD45-positive immune cells in cochlea. Increases in CXCL1 was time-dependent in the spiral ganglion neurons and organ of Corti and was associated with progressive increases in CD45, CD68 and IBA1-positive immune cells. Trans-tympanic administration of SB225002, a chemical inhibitor of CXCR2 (receptor target for CXCL1) reduced immune cell migration, protected against cisplatin-induced hearing loss and preserved hair cell integrity. We show that SB225002 reduced the expression of CXCL1, NOX3, iNOS, TNF-α, IL-6 and COX-2. Similarly, knockdown of CXCR2 by trans-tympanic administration of CXCR2 siRNA protected against hearing loss and loss of outer hair cells and reduced ribbon synapses. In addition, SB225002 reduced the expression of inflammatory mediators induced by cisplatin. These results implicate the CXCL1 chemokine as an early player in cisplatin ototoxicity, possibly by initiating the immune cascade, and indicate that CXCR2 is a relevant target for treating cisplatin ototoxicity. Frontiers Media S.A. 2023-03-31 /pmc/articles/PMC10102581/ /pubmed/37063917 http://dx.doi.org/10.3389/fimmu.2023.1125948 Text en Copyright © 2023 Al Aameri, Alanisi, Oluwatosin, Al Sallami, Sheth, Alberts, Patel, Rybak and Ramkumar https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Al Aameri, Raheem F. H.
Alanisi, Entkhab M. A.
Oluwatosin, Adu
Al Sallami, Dheyaa
Sheth, Sandeep
Alberts, Ian
Patel, Shree
Rybak, Leonard P.
Ramkumar, Vickram
Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title_full Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title_fullStr Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title_full_unstemmed Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title_short Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity
title_sort targeting cxcl1 chemokine signaling for treating cisplatin ototoxicity
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102581/
https://www.ncbi.nlm.nih.gov/pubmed/37063917
http://dx.doi.org/10.3389/fimmu.2023.1125948
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