Dual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea.

Jose M Bermúdez-Muñoz,Ángela García-Mato,Manuel Serrano,Daniel Muñoz-Espín,Adelaida M Celaya,Lourdes Rodríguez-De La Rosa,Isabel Varela-Nieto

doi:10.3390/antiox10091351

Abstract

Stress-activated protein kinases (SAPK) are associated with sensorineural hearing loss (SNHL) of multiple etiologies. Their activity is tightly regulated by dual-specificity phosphatase 1 (DUSP1), whose loss of function leads to sustained SAPK activation. Dusp1 gene knockout in mice accelerates SNHL progression and triggers inflammation, redox imbalance and hair cell (HC) death. To better understand the link between inflammation and redox imbalance, we analyzed the cochlear transcriptome in Dusp1−/− mice. RNA sequencing analysis (GSE176114) indicated that Dusp1−/− cochleae can be defined by a distinct profile of key cellular expression programs, including genes of the inflammatory response and glutathione (GSH) metabolism. To dissociate the two components, we treated Dusp1−/− mice with N-acetylcysteine, and hearing was followed-up longitudinally by auditory brainstem response recordings. A combination of immunofluorescence, Western blotting, enzymatic activity, GSH levels measurements and RT-qPCR techniques were used. N-acetylcysteine treatment delayed the onset of SNHL and mitigated cochlear damage, with fewer TUNEL+ HC and lower numbers of spiral ganglion neurons with p-H2AX foci. N-acetylcysteine not only improved the redox balance in Dusp1−/− mice but also inhibited cytokine production and reduced macrophage recruitment. Our data point to a critical role for DUSP1 in controlling the cross-talk between oxidative stress and inflammation.

Highlights

We recently showed that mice with genetic deficiency of Dusp1 present with exacerbated inflammation and generalized hair cell (HC) and spiral ganglion neurons (SGNs) loss along aging, providing a good model of premature sensorineural hearing loss (SNHL) [9]
A similar NAC response was observed for the expression levels of Tgfβ1, Mpo, Foxp3 and Overall, these results suggest that the induction of inflammatory gene expression observed in Dusp1−/− cochleae was secondary to the oxidative imbalance, as it could be repressed, albeit incompletely, with NAC
We provide new insight into the role of dual-specificity phosphatase 1 (DUSP1) in the cochlea using a combination of transcriptomics and antioxidant treatment of Dusp1-deficient mice

Summary

Introduction

Progressive sensorineural hearing loss (SNHL) is a bilateral and gradual impairment of hearing as a consequence of cochlear degeneration, most commonly resulting from the death of mechanosensitive hair cells (HCs) or/and spiral ganglion neurons (SGNs), which are both irreplaceable in mammals. Genetic inheritance in combination with environmental and lifestyle factors determines the onset, severity and progression of SNHL [1], which is the most frequent sensory impairment in the elderly. The World Health Organization estimates that over 700 million people worldwide will experience disabling hearing loss by. Preventive therapies to suppress the molecular mechanisms responsible for HC and SGN death are the most promising treatment options to avert irreversible damage

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