Abstract
Inflammatory reaction plays a crucial role in the pathophysiology of acquired hearing loss such as ototoxicity and labyrinthitis. In our earlier work, we showed the pivotal role of otic fibrocytes in cochlear inflammation and the critical involvement of proinflammatory cytokines in cisplatin ototoxicity. We also demonstrated that otic fibrocytes inhibit monocyte chemoattractant protein 1 (CCL2) upregulation in response to interleukin-10 (IL-10) via heme oxygenase 1 (HMOX1) signaling, resulting in suppression of cochlear inflammation. However, it is still unclear how IL-10 affects inflammation-mediated cochlear injury. Here we aim to determine how hypochlorous acid, a model inflammation mediator affects cochlear cell viability and how IL-10 affects hypochlorous acid-mediated cochlear cell injury. NaOCl, a sodium salt of hypochlorous acid (HOCl) was found to induce cytotoxicity of HEI-OC1 cells in a dose-dependent manner. Combination of hydrogen peroxide and myeloperoxidase augmented cisplatin cytotoxicity, and this synergism was inhibited by N-Acetyl-L-cysteine and ML-171. The rat spiral ligament cell line (RSL) appeared to upregulate the antioxidant response element (ARE) activities upon exposure to IL-10. RSL cells upregulated the expression of NRF2 (an ARE ligand) and NR0B2 in response to CoPP (a HMOX1 inducer), but not to ZnPP (a HMOX1 inhibitor). Adenovirus-mediated overexpression of NR0B2 was found to suppress CCL2 upregulation. IL-10-positive cells appeared in the mouse stria vascularis 1 day after intraperitoneal injection of lipopolysaccharide (LPS). Five days after injection, IL-10-positive cells were observed in the spiral ligament, spiral limbus, spiral ganglia, and suprastrial area, but not in the stria vascularis. IL-10R1 appeared to be expressed in the mouse organ of Corti as well as HEI-OC1 cells. HEI-OC1 cells upregulated Bcl-xL expression in response to IL-10, and IL-10 was shown to attenuate NaOCl-induced cytotoxicity. In addition, HEI-OC1 cells upregulated IL-22RA upon exposure to cisplatin, and NaOCl cytotoxicity was inhibited by IL-22. Taken together, our findings suggest that hypochlorous acid is involved in cochlear injury and that IL-10 potentially reduces cochlear injury through not only inhibition of inflammation but also enhancement of cochlear cell viability. Further studies are needed to determine immunological characteristics of intracochlear IL-10-positive cells and elucidate molecular mechanisms involved in the otoprotective activity of IL-10.
Highlights
Inflammation is a tightly controlled process because excessive inflammation potentially leads to unintended tissue injury
CoPP, not ZnPP, was found to upregulate NRF2 expression (Figure 2B), and heme oxygenase 1 (HMOX1) expression was upregulated by IL-10 (Figure 2C). These findings indicate an existence of the NRF2-mediated positive feedback loop in otic fibrocytes, which may be required for maintaining IL-10-induced HMOX1 upregulation, through bypassing the p38 MAPK pathway
Multiple mechanisms are involved in the damage and survival of the cochlear sensorineural tissue (Wong and Ryan, 2015), and understanding those mechanisms would facilitate the development of a novel clinical tool for the management of acquired sensorineural hearing loss (SNHL)
Summary
Inflammation is a tightly controlled process because excessive inflammation potentially leads to unintended tissue injury. Inflammation is increasingly recognized to contribute to the pathophysiology of acquired sensorineural hearing loss (SNHL) such as ototoxicity, given that lipopolysaccharide (LPS)induced inflammatory response aggravates cisplatin ototoxicity as well as the synergistic ototoxicity of kanamycin and furosemide (Oh et al, 2011; Hirose et al, 2014) It has not been fully understood how inflammatory reaction itself induces cochlear injury. Due to its powerful oxidative property, there is a risk of host tissue injuries when associated with excessive inflammatory reactions (Pullar et al, 2000) It is unclear whether hypochlorous acid is ototoxic and contributes to inflammationmediated cochlear injury
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