GSE176114
Dusp1 deletion unveils its central role in the regulation of redox homeostasis and inflammation in the mouse cochlea
Stress-activated protein kinases (SAPK) have been associated with sensorineural hearing loss (SNHL) of multiple etiologies.  The activity of these kinases is tightly regulated by the dual-specificity phosphatase 1 (DUSP1), thus, DUSP1 loss of function leads to the sustained activation of SAPK. In the hearing organ, DUSP1 is an indispensable component of the stress response machinery, and its deficit accelerates SNHL progression, triggers the inflammatory response and promotes hair cell (HC) and spiral neurons (SGN) death. Here, we have studied the link between inflammation and redox imbalance in the cochlea by further characterizing the transcriptome of the Dusp1-/- mouse.  RNAseq and subsequent GSEA indicated that Dusp1-/- mice present a distinct gene expression pattern of key cellular programs, including altered expression of genes of the inflammatory response and glutathione metabolism.  To dissociate both components, Dusp1-/- mice were treated with the antioxidant N-acetylcysteine (NAC). Treatment with NAC delayed the onset of SNHL and reduced cochlear damage. Less HC were TUNEL+ and SGN showed less p-H2AX foci. NAC treatment not only improved redox balance but also reduced cytokine production and macrophage recruitment in Dusp1-/ -mice. In conclusion, our data point to DUSP1 as an essential node to control the cross-regulation of oxidative stress and inflammation. Overall design: Cochlear mRNA profiles of 5 and 8-months-old wild type (WT) and Dusp1-/- mice