Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity.
Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity.
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DOI：
10.3389/fimmu.2023.1125948
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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顺铂是一种用于实体肿瘤治疗的化疗药物，如肺癌、膀胱癌、头颈癌、卵巢癌和睾丸癌。然而，顺铂诱导的耳毒性限制了该药物在癌症患者中的应用，特别是当需要增加剂量时。耳毒性通过DNA损伤、活性氧（ROS）的产生以及随之而来的caspase的激活、谷氨酸兴奋性毒性、炎症、细胞凋亡和/或坏死与耳蜗细胞死亡相关。先前的研究已经证实了CXC趋化因子在顺铂耳毒性中的作用。在这项研究中，我们研究了CXCL1的作用，CXCL1是一种细胞因子，在顺铂给药后24小时在血清和耳蜗中升高。顺铂治疗的成年雄性Wistar大鼠表现出明显的听力损失，通过听觉脑干反应（ABRs）、毛细胞损失和带状突触损失来评估。免疫组织化学研究评估了CXCL1的水平以及耳蜗中CD68和cd45阳性免疫细胞的增加。在螺旋神经节神经元和Corti器官中，CXCL1的增加是时间依赖性的，并且与CD45、CD68和iba1阳性免疫细胞的进行性增加有关。SB225002是一种CXCR2 （CXCL1受体靶点）的化学抑制剂，经鼓室给药可减少免疫细胞迁移，防止顺铂诱导的听力损失，并保持毛细胞的完整性。我们发现SB225002降低了CXCL1、NOX3、iNOS、TNF-α、IL-6和COX-2的表达。同样，通过跨鼓室给药CXCR2 siRNA来敲低CXCR2可以防止听力丧失、外毛细胞丧失和带状突触减少。此外，SB225002可降低顺铂诱导的炎症介质的表达。这些结果暗示CXCL1趋化因子可能通过启动免疫级联在顺铂耳毒性中起早期作用，并表明CXCR2是治疗顺铂耳毒性的相关靶点。
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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