Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity

Cathy Yea Won Sung; Naoki Hayase; Peter S T Yuen; John Lee; Katharine Fernandez; Xuzhen Hu; Hui Cheng; Robert A Star; Mark E Warchol; Lisa L Cunningham

doi:10.1126/sciadv.adk9878

Back

Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity

Journal article

Open access

Peer reviewed

Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity

Cathy Yea Won Sung, Naoki Hayase, Peter S T Yuen, John Lee, Katharine Fernandez, Xuzhen Hu, Hui Cheng, Robert A Star, Mark E Warchol and Lisa L Cunningham

Science advances, Vol.10(30), p.eadk9878

07/26/2024

DOI: 10.1126/sciadv.adk9878

PMCID: PMC11268410

PMID: 39047106

Files and links (1)

url

https://doi.org/10.1126/sciadv.adk9878View

Published (Version of record) Open Access

Abstract

Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.

Aminopyridines

Animals

Antineoplastic Agents - adverse effects

Antineoplastic Agents - toxicity

Cisplatin - adverse effects

Cisplatin - toxicity

Cochlea - drug effects

Cochlea - metabolism

Cochlea - pathology

Hearing Loss - chemically induced

Hearing Loss - prevention & control

Kidney - drug effects

Kidney - metabolism

Kidney - pathology

Kidney Diseases - chemically induced

Kidney Diseases - pathology

Kidney Diseases - prevention & control

Macrophages - drug effects

Macrophages - metabolism

Mice

Mice, Inbred C57BL

Ototoxicity - etiology

Ototoxicity - prevention & control

Pyrroles

Details

Title: Subtitle: Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity
Creators: Cathy Yea Won Sung - National Institute on Deafness and Other Communication Disorders
Naoki Hayase - National Institute of Diabetes and Digestive and Kidney Diseases
Peter S T Yuen - National Institute of Diabetes and Digestive and Kidney Diseases
John Lee - National Institute on Deafness and Other Communication Disorders
Katharine Fernandez - National Institute on Deafness and Other Communication Disorders
Xuzhen Hu - National Institute of Diabetes and Digestive and Kidney Diseases
Hui Cheng - National Institute on Deafness and Other Communication Disorders
Robert A Star - National Institute of Diabetes and Digestive and Kidney Diseases
Mark E Warchol - Washington University in St. Louis
Lisa L Cunningham - National Institute on Deafness and Other Communication Disorders
Resource Type: Journal article
Publication Details: Science advances, Vol.10(30), p.eadk9878
DOI: 10.1126/sciadv.adk9878
PMID: 39047106
PMCID: PMC11268410
NLM abbreviation: Sci Adv
ISSN: 2375-2548
eISSN: 2375-2548
Grant note: ZIC DC000080 / Intramural NIH HHS ZIA DK043403 / Intramural NIH HHS R01 DC006283 / NIDCD NIH HHS ZIA DC000079 / Intramural NIH HHS
Language: English
Date published: 07/26/2024
Academic Unit: Biology
Record Identifier: 9984961046602771

Metrics

3 Record Views