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

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cam.issuedOnline2021-08-25
dc.contributor.authorBermúdez-Muñoz, Jose M
dc.contributor.authorCelaya, Adelaida M
dc.contributor.authorGarcía-Mato, Ángela
dc.contributor.authorMuñoz-Espín, Daniel
dc.contributor.authorRodríguez-de la Rosa, Lourdes
dc.contributor.authorSerrano, Manuel
dc.contributor.authorVarela-Nieto, Isabel
dc.contributor.orcidBermúdez-Muñoz, Jose M [0000-0002-6034-9285]
dc.contributor.orcidGarcía-Mato, Ángela [0000-0001-9961-8377]
dc.contributor.orcidRodríguez-de la Rosa, Lourdes [0000-0002-7518-6036]
dc.contributor.orcidSerrano, Manuel [0000-0001-7177-9312]
dc.contributor.orcidVarela-Nieto, Isabel [0000-0003-3077-0500]
dc.date.accessioned2021-10-30T01:12:30Z
dc.date.available2021-10-30T01:12:30Z
dc.date.issued2021-08-25
dc.date.updated2021-10-30T01:12:29Z
dc.description.abstractStress-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.
dc.identifier.citationAntioxidants (Basel, Switzerland), volume 10, issue 9
dc.identifier.doi10.17863/CAM.77528
dc.identifier.eissn2076-3921
dc.identifier.issn2076-3921
dc.identifier.otherPMC8467085
dc.identifier.other34572983
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330084
dc.languageeng
dc.language.isoeng
dc.publisherMDPI AG
dc.publisher.urlhttp://dx.doi.org/10.3390/antiox10091351
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2076-3921
dc.sourcenlmid: 101668981
dc.subjectN-acetylcysteine
dc.subjectRNAseq
dc.subjectantioxidants
dc.subjectapoptosis
dc.subjectglutathione
dc.subjecthearing
dc.subjectinflammation
dc.subjectmitochondria
dc.subjectreactive oxygen species (ROS)
dc.titleDual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea.
dc.typeArticle
dcterms.dateAccepted2021-08-23
prism.publicationNameAntioxidants (Basel)
pubs.funder-project-idMedical Research Council (MR/R000530/1)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3390/antiox10091351

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