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

This article belongs to the Special Issue Oxidative Stress and Inflammation in Deafness: Current and Future Therapy.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 inflammationThis work was funded by FEDER/B2017/BMD-3688-MULTITARGET&VIEWCM and 0551-PSL-6-E NITROPROHEAR grants to I.V.-N., J.M.B.-M., Á.G.-M. and L.R.-d.l.R. held SAF2017-HEARCODE, FPU (FPU16/03308; MECD) and CIBERER (Institute of Health Carlos III) contracts, respectively, co-financed with FEDER funds. Work by D.M.-E. and M.S. was funded by grant SAF2017-82613-R from the Spanish Ministry of Science co-funded by the European Regional Development Fund (ERDF). Work in the laboratory of M.S. was also funded by the IRB and “laCaixa” Foundation, and by grants from the European Research Council (ERC-2014-AdG/669622), and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282. D.M.-E. laboratory is supported by the Cancer Research UK (CRUK) Cambridge Centre Early Detection Programme (RG86786), by a CRUK Programme Foundation Award (C62187/A29760), by a CRUK Early Detection OHSU Project Award (C62187/A26989), and by a Medical Research Council (MRC) New Investigator Research Grant (NIRG) (MR/R000530/1)