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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Bermúdez-Muñoz, Jose M  ORCID logo  https://orcid.org/0000-0002-6034-9285
Celaya, Adelaida M 
García-Mato, Ángela  ORCID logo  https://orcid.org/0000-0001-9961-8377
Muñoz-Espín, Daniel 
Rodríguez-de la Rosa, Lourdes  ORCID logo  https://orcid.org/0000-0002-7518-6036

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.

Description

Keywords

N-acetylcysteine, RNAseq, antioxidants, apoptosis, glutathione, hearing, inflammation, mitochondria, reactive oxygen species (ROS)

Journal Title

Antioxidants (Basel)

Conference Name

Journal ISSN

2076-3921
2076-3921

Volume Title

Publisher

MDPI AG
Sponsorship
Medical Research Council (MR/R000530/1)
Cancer Research UK (C62187/A29760)