Dexamethasone attenuates TNF-α-induced ototoxicity via Peroxiredoxin 6 upregulation in murine auditory hair cells and cochlea of noise-exposed mice

Tumor necrosis factor-alpha (TNF-α) is one of the major cytokines that triggers damage to auditory hair cells, exerting sensorineural hearing loss. Dexamethasone (DEX) is widely used to reduce inflammation and is known to upregulate the expression of Peroxiredoxin 6 (Prdx6), an antioxidant enzyme. We previously reported that DEX pretreatment protected auditory hair cells from TNF-α-triggered damage. However, the protective molecular mechanism of DEX against TNF-α-triggered ototoxicity remains to be elucidated. In this study, we investigated the involvement of Prdx6 in the protective effect of DEX on TNF-α-triggered ototoxicity. DEX pretreatment resulted in reduced TNF-α-induced intracellular and mitochondrial reactive oxygen species (ROS) accumulation, pro-inflammatory cytokine expression, and NF-κB signaling activation. The Prdx6 expression level was decreased in TNF-α-treated cells but increased in DEX-treated cells. Moreover, DEX pretreatment elevated the expression of Prdx6 and the glucocorticoid receptor. Chromatin immunoprecipitation and luciferase reporter assays demonstrated transactivation of the Prdx6 gene by DEX pretreatment. In noise-exposed mice, we observed increased auditory brainstem response (ABR) thresholds, decreased numbers of outer hair cells (OHCs), increased expression of TNF-α, IL-1β, and phospho-p65 (p-p65) protein (an NF-κB subunit), and reduced expression of Prdx6 protein. DEX pretreatment prior to noise exposure resulted in a suppressed elevation of ABR threshold and reduced damage to OHCs. Furthermore, increased GR and Prdx6 expression and a weaker expression of TNF-α, IL-1β, and p-p65 were observed in cochlear tissues. These findings suggested that DEX pretreatment suppresses ROS- and inflammation-related signaling through transcriptional upregulation of Prdx6 , subsequently attenuating TNF-α-triggered ototoxicity. • DEX reduced TNF-α-triggered ROS and the expression of inflammation-related proteins. • DEX-activated GR transactivates Prdx6 via a GRE region within the Prdx6 promoter. • DEX pre-injection prevents noise-induced hearing loss in mice via increased Prdx6 expression.