Interleukin 8 exacerbates age-related hearing loss through regulating perivascular-resident macrophage-like melanocytes viability and the permeability of the endothelial cells.

The etiology and mechanism causing Age-related hearing loss (ARHL) are not understood. This study aimed to investigate the molecular mechanism of interleukin 8 (IL-8) associated with ARHL. Sera content of IL-8 was significantly higher in patients with ARHL than normal volunteers and had a positive association with disease severity of ARHL. Human IL-8 (hIL-8) could exacerbate the progressive ARHL with time increase and promoted apoptosis of hair cells in cochlea. As the important component in maintaining the integrity of the blood-labyrinth barrier (BLB) and hearing function, cell viability of perivascular-resident macrophage-like melanocytes (PVM/Ms) was restrained while apoptosis of PVM/Ms was enhanced in the presence of hIL-8. Using a cell culture-based in vitro model, the permeability of the endothelial cells (ECs) monolayer increased markedly in the presence of IL-8-treated PVM/Ms or PVM/Ms-derived from LV5-hIL-8 mice as compared with the presence of PVM/Ms-derived from wild type (WT) mice or 12-months WT mice. Mechanistically, IL-8 exposure enhanced the expression of histone deacetylase 3 (HDAC3) in PVM/Ms and HDAC3 inhibitor significantly blocked the permeability of the ECs in the presence of IL-8-treated PVM/Ms. Besides, HDAC3 inhibitor had a protective effect on hIL-8-launched ARHL in mice. Collectively, the elevated of serum IL-8 in ARHL patients activated the activity of HDAC3 in PVM/Ms, subsequently increased the permeability of the ECs, resulting in the impairments of the BLB and hair cells in cochlea. Possibly, IL-8 could be used in the diagnosis of ARHL and these findings might help to identify the clinical therapeutic direction for ARHL.