Dual-specificity phosphatase 26-dificient neurons are susceptible to oxygen-glucose deprivation/reoxygenation-evoked apoptosis and proinflammatory response by affecting the TAK1-medaited JNK/P38 MAPK pathway.

Abstract

Dual-specificity phosphatase 26 (DUSP26) is linked to a broad range of human disorders as it affects numerous signaling cascades. However, the involvement of DUSP26 in ischemic stroke has not been explored. Here, we investigated DUSP26 as a key mediator of oxygen-glucose deprivation/reoxygenation (OGD/R)-associated neuronal injury, an in vitro model for investigating ischemic stroke. A decline in DUSP26 occurred in neurons suffering from OGD/R. A deficiency in DUSP26 rendered neurons more susceptible to OGD/R by aggravating neuronal apoptosis and inflammation, while the overexpression of DUSP26 blocked OGD/R-evoked neuronal apoptosis and inflammation. Mechanistically, enhanced phosphorylation of transforming growth factor-β-activated kinase 1 (TAK1), c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) was evidenced in DUSP26-deficient neurons suffering from OGD/R, whereas the opposite effects were observed in DUSP26-overexpressed neurons. Moreover, the inhibition of TAK1 abolished the DUSP26-deficiency-elicited activation of JNK and P38 MAPK and exhibited anti-OGD/R injury effects in DUSP26-deficiency neurons. Results from these experiments show that DUSP26 is essential for neurons in defending against OGD/R insult, while neuroprotection is achieved by restraining the TAK1-mediated JNK/P38 MAPK pathway. Therefore, DUSP26 may serve as a therapeutic target for the management of ischemic stroke.