Inhibition of inner ear macrophage phagocytosis alleviates cisplatin-induced ototoxicity

The immune response is considered a significant pathological mechanism of inner ear damage. However, the role of macrophages, as key components of immune cells, in immunity in the inner ear remains elusive. Evidence from other organs indicates that phagocytosis, a core function of macrophages, plays a crucial role in maintaining homeostasis, development, and tissue repair regeneration. However, it has rarely been studied in the inner ear. This field may currently hold new insights. In this study, we aimed to investigate the immunological contribution of resident macrophages in the inner ear to cisplatin-induced ototoxicity. By using clodronate liposomes and cytochalasin to deplete macrophages or inhibit macrophage phagocytosis locally, we first elucidated the dynamic changes in the immune state of inner ear macrophages during cisplatin injury through multimodal and multidimensional approaches. High-spatiotemporal-resolution single-cell analysis and real-time imaging of macrophages during zebrafish hair cell death identified proinflammatory subsets during cisplatin injury. We found that macrophage activation through phagocytosis synergized with the inflammatory response and that inhibiting macrophage phagocytosis could ameliorate cisplatin-induced ototoxicity. Finally, we discuss how the highly plastic phagocytic function of resident macrophages in the inner ear holds potential for the development of strategies for treating cisplatin-induced hearing loss.