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

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.

DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway

“…Studies have shown that DUSP1 plays an important role in regulation of apoptosis and inflammatory response 17 , 18 . In this study we examine whether BCG infection upregulates DUSP1 expression and whether DUSP1 is involved in BCG-induced apoptosis and inflammatory response.…”

DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway

“…BCG infection induces apoptosis in THP-1 cells and promotes the expression of DUSP1 and proin ammatory cytokines. Studies have shown that DUSP1 plays an important role in regulation of apoptosis and in ammatory response 13,14 . In this study we examine whether BCG infection upregulates DUSP1 expression and whether DUSP1 is involved in BCG-induced apoptosis and in ammatory response.…”

DUSP1 promotes muscle atrophy by inhibiting myocyte differentiation in cachectic patients

“…It has been established that DUSP1,among the 10 family members, plays a regulatory role in a variety of cellular responses, especially in inflammation. Prior reports have indicated that DUSP1 regulates oral cancer-associated inflammation and leukocyte infiltration ( 26 ). However, to date, the role of DUSP1 in muscle atrophy of cancer cachexia remains unclear.…”