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.

中文翻译：

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巨噬细胞耗竭可防止顺铂引起的耳毒性和肾毒性


顺铂是一种广泛使用的抗癌药物，具有显着的副作用，包括耳毒性和肾毒性。巨噬细胞是耳蜗和肾脏中主要的常驻免疫细胞，是炎症和组织修复反应的重要驱动因素。为了研究巨噬细胞在顺铂引起的毒性中的作用，我们使用美国食品和药物管理局批准的集落刺激因子 1 受体抑制剂 PLX3397 来消除组织驻留巨噬细胞。单独使用顺铂治疗的小鼠出现严重的听力损失（耳毒性）和肾损伤（肾毒性）。巨噬细胞消融可显着减少听力损失，并提高外毛细胞的存活率。巨噬细胞消融还可以防止顺铂引起的肾毒性，肾小管损伤和纤维化显着减少就证明了这一点。从机制上讲，我们的数据表明，巨噬细胞消融对顺铂引起的耳毒性和肾毒性的保护作用是通过减少内耳和肾脏中铂的积累来介导的。总之，我们的数据表明，组织驻留巨噬细胞的消融是减轻顺铂诱导的耳毒性和肾毒性的重要策略。