CCR2-dependent recruitment of SPP1+ macrophages promoted noise-induced hearing loss via pyroptosis

<title>Abstract</title> <p>Recent studies have highlighted the pivotal role of macrophages in the cochlea following acoustic stimulation. Here, we investigated the contribution of secreted phosphoprotein 1 (SPP1, osteopontin)-expressing macrophages to noise-induced hearing loss (NIHL). Single-cell RNA sequencing of murine cochleae revealed expansion of a macrophage subset characterized by high expression of Ccr2 and Spp1 at three days post-noise exposure. Genetic ablation of Ccr2 or Spp1 attenuated noise-induced auditory deficits. Cell–cell interaction analysis suggested that SPP1 enhances the phagocytic activity of SPP1⁺ macrophages and promotes their recruitment to cochlear hair cells and neurons. Immunofluorescence staining and ELISA demonstrated that pyroptosis of SPP1⁺ macrophages was associated with local inflammation and tissue damage. Pharmacological inhibition of SPP1 or CCR2 partially prevented noise-induced hearing loss. Collectively, these findings suggest that SPP1⁺ macrophages may represent a potential therapeutic target for NIHL.</p>